Arylsulfonamide derivatives for use as ccr3 antagonists in the treatment of inflammatory and immunological disorders

ABSTRACT

The present invention relates to a sulfonamide derivative which is useful as an active ingredient of pharmaceutical preparations. The sulfonamide derivatives of the present invention have CCR3 (CC type chemokine receptor) antagonistic activity, and can be used for the prophylaxis and treatment of diseases associated with CCR3 activity, in particular for the treatment of asthma, atopic dermatitis, allergic rhinitis and other inflammatory/immunological disorders.

TECHNICAL FIELD

The present invention relates to a sulfonamide derivative which is useful as an active ingredient of pharmaceutical preparations. The sulfonamide derivatives of the present invention have CCR3 (CC type chemokine receptor 3) antagonistic activity, and can be used for the prophylaxis and treatment of diseases associated with CCR3 activity, in particular for the treatment of asthma, atopic dermatitis, allergic rhinitis and other inflammatory/immunological disorders.

BACKGROUND ART

Chemokines are chemotactic cytokines of which major functions are migration of inflammatory cells that express relevant chemokine receptors on their surfaces to sites of inflammation, and activation of inflammatory cells. There are two classes of chemokines, C-X-C (.alpha.) and C-C (i), depending on whether the first two cysteines are separated by a single amino acid (C-X-C) or are adjacent (C-C).

One of the C-C family of chemokines, eotaxin, is an 8.4 kDa (74 amino acid) polypeptide and binds with high affinity solely to the receptor CCR3. In vitro and in vivo eotaxin causes chemotaxis of inflammatory cells expressing CCR3 [Elsner J., Hochstetter R., Kimming D. and Kapp A.: Human eotaxin represents a potent activator of the respiratory burst of human eosinophils. Eur. J. Immunol., 26: 1919-1925, 1996.].

The chemokine receptor CCR3 is a G protein-coupled, seven transmembrane domain receptor (GPCR) which binds to known ligands, in addition to eotaxin, including eotaxin-2 (CCL24), RANTES (CCL5), MCP-3 (CCL7) and MCP-4 (CCL13). CCR3 is expressed on inflammatory cells relevant to the chronic asthma pathology. Such inflammatory cells include Eosinophils [Sabroe I., Conroy D. M., Gerard N. P., Li Y., Collins P. D., Post T. W., Jose P. J., Williams T. J., Gerard C. J., Ponath P. D. J. Immunol. 161: 6139-6147, 1998], basophils [Uguccioni M., Mackay C. R., Ochensberger B., Loetscher P., Rhis S., LaRosa G. J., Rao P., Ponath P. D., Baggiolini M., Dahinden C. A. J. Clin. Invest. 100: 1137-1143, 1997], Th2 cells [Sallusto F., Mackay C. R., Lanzavecchia A. Science. 277: 2005-2007, 1997), alveolar macrophages [Park I. W., Koziel H., Hatch W., Li X., Du B., Groopman J. E. Am. J. Respir. Cell Mol. Biol. 20:864-71, 1999] and mast cells [Oliveira S. H. and Lukacs N. W. Inflamm. Res. 50: 168-174, 2001]. Very recently, it was reported that BEAS-2B, an epithelial cell line, stimulated with TNF-α and IFN-γ, expressed CCR3 [Stellato C., Brummet M. E., Plitt J. R., Shahabuddin S., Baroody F. M., Liu M., Ponath P. D., and Beck L. A. J. Immunol., 166: 1457-1461, 2001.].

In animal models, eotaxin-knockout mice showed decreased eosinophilia after antigen challenge [Rothenberg M. E., MacLean J. A., Pearlman E., Luster A. D. and Leder P. J. Exp. Med., 185: 785-790, 1997] and in IL5-/eotaxin-double knock-out mice there is no eosinophilia or AHR in response to antigen challenge [Foster P. S., Mould A. W., Yang M., Mackenzie J., Mattes J., Hogan S. P., Mahalingam S., Mckenzie A. N. J., Rothenberg M. E., Young I. G., Matthaei K. L. and Webb D. C. Immunol. Rev., 179, 173-181, 2001]. Clinically, expression of eotaxin and CCR3 mRNA and protein is observed in the lung tissues of atopic asthmatics and is associated with AHR, reduced FEV₁ and lung eosinophilia [Ying S., Robin D. S., Meng Q., Rottman J., Kennedy R., Ringler D. J., Mackay C. R., Daugherty B. L., Springer M. S., Durham S. R., Williams T. J. and Kay A. B.: Enhanced expression of eotaxin and CCR3 mRNA and protein in atopic asthma. Association with airway hyperresponsiveness and predominant colocalization of eotaxin mRNA to bronchial epithelial and endothelial cells. Eur. J. Immunol., 27, 3507-3516, 1997; Lamkhioued Renzi P. M., AbiYounes S., GarciaZepada E. A., Allakhverdi Z., Ghaffar O., Rothenberg M. D., Luster A. D. and Hamid Q.: Increased expressions of eotaxin in bronchoalveolar lavage and airways of asthmatics contributes to the chemotaxis of eosinophils to the site of inflammation. J. Immunol., 159: 4593-4601, 1997; Jahnz-Royk K., Plusa T. and Mierzejewska J.: Eotaxin in serum of patients with asthma or chronic obstructive pulmonary disease: relationship with eosinophil cationic protein and lung function. Mediators of Inflammation, 9: 175-179, 2000]. In addition, in allergic rhinitis, CCR3-expressing Th2 lymphocytes co-localize with eosinophils in nasal polyps in close proximity to eotaxin-expressing cells [Gerber B. O., Zanni M. P., Uguccioni M., Loetscher M., Mackay C. R., Pichler W. J., Yawalkar N., Baggiolini M. and Moser B.: Functional expression of the eotaxin receptor CCR3 in T lymphocytes co-localizing with eosinophils. CURRENT BIOLOGY 7: 836-843, 1997]. Moreover, viral infections (RSV, influenza virus) which are known risk factors in asthma, result in increased eotaxin expression in lung tissue which is correlated with tissue eosinophilia [Matsukura S., Kokubo F., Kubo H., Tomita T., Tokunaga H., Kadokura M., Yamamoto T., Kuroiwa Y., Ohno T., Suzaki H. and Adachi M.: Expression of RANTES by normal airway epithelial cells after influenza virus A infection. Am. J. Respir. Cell and Mol. Biol., 18: 255-264, 1998; Saito T., Deskin R. W., Casola A., Haeberle H., Olszewska B., Ernest P. B., Alam R., Ogra P. L. and Garofalo R.: Selective regulation of chemokine production in human epithelial cells. J. Infec. Dis., 175: 497-504, 1997].

Thus the binding of CCR3 and related chemokine including eotaxin has been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma, rhinitis, and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and athero-sclerosis. It is also implicated that binding of CCR3 and related chemokine is an important factor of virus infections including HIV [(Marone G, de Paulis A, Florio G, Petraroli A, Rossi F, Triggiani M.: Int Arch Allergy Immunol 2001 June;125(2)/89-95), (Li Y et al.,: Blood 2001 Jun. 1; 97(11):3484-90), and (Marone G, Florio G, Petraroli A, Triggiani M, de Paulis A: Trends Immunol 2001 May;22 (5):229-32)], lung granuloma (Ruth J H, Lukacs N W, Warmington K S, Polak T J, Burdick M, Kunkel S L, Strieter R M, Chensue S W:J Immunol 1998 Oct. 15;161 (8):4276-82), and Alzheimer's diseases (Xia M Q, Qin S X, Wu L J, Mackay C R, and Hyman B T: Am J Pathol 1998 July;153 (1):31-37).

Therefore, CCR3 is an important target and antagonism of CCR3 is likely to be effective in the treatment of such inflammatory and immunoregulatory disorders and diseases.

WO 00/76514 and WO 00/76513 disclose cyclopentyl modulators of chemokine receptors including CCR3 activity represented by the general formula:

wherein

X″, x, y, R^(1,), R^(2,), R^(3,), R^(4,), R^(5,), R⁶, R⁷, and R⁸, are defined in the application.

Other applications also disclose CCR3 modulators.

However, none of the reference and other reference discloses simple sulfonamide derivatives having CCR3 antagonistic activity.

The development of a compound having effective CCR3 antagonistic activity and can be used for the prophylaxis and treatment of diseases associated with CCR3 activity has been desired.

SUMMARY OF THE INVENTION

As the result of extensive studies on chemical modification of sulfonamide derivatives, the present inventors have found that the compounds of the structure related to the present invention have unexpectedly excellent CCR3 antagonistic activity. The present invention has been accomplished based on these findings.

This invention is to provide novel sulfonamide derivatives shown by the following formula (I), its tautomeric and stereoisomeric form, and the salts thereof.

-   X represents phenyl, which is substituted by 0 to 5 substituents     independently selected from the group consisting of R¹, R², R³, R⁴     and R⁰ or pyridine, which is substituted by 0 to 5 substituents     independently selected from the group consisting of R¹, R², R³ and     R⁴     -   wherein     -   R¹ is hydrogen, halogen, hydroxy, straight- or branched-C₁₋₆         alkyl optionally substituted by mono, di or tri halogen,         straight- or branched-C₁₋₆ alkoxy, straight- or branched-C₁₋₆         alkoxy carbonyl, amino, straight- or branched-C₁₋₆ alkylamino,         di(straight- or branched-C₁₋₆ alkyl)amino, straight- or         branched-C₁₋₆ alkanoyl, nitro, or phenyl,     -   R² is hydrogen, halogen, straight- or branched-C₁₋₆ alkyl         optionally substituted by mono, di or tri halogen, straight- or         branched-C₁₋₆ alkoxy, or cyano,     -   or     -   R¹ and R² together form benzene ring or C₅₋₈ cycloalkyl fused to         the adjacent phenyl or pyridine,     -   R³ is hydrogen, halogen, or straight- or branched-C₁₋₆ alkyl,     -   R⁴ is hydrogen, halogen, or straight- or branched-C₁₋₆ alkyl,     -   R⁰ is hydrogen, halogen, or straight- or branched-C₁₋₆ alkyl,     -   Y represents O, NH, NCH₃ S, S(O), or SO₂;     -   Z¹ represents CH or N;     -   Z² represents CH or N     -   with the proviso that both Z¹ and Z² cannot be N at the same         time;     -   R⁵ represents hydrogen, halogen, hydroxy, straight- or         branched-C₁₋₆ alkyl optionally substituted by mono, di or tri         halogen or hydroxy, straight- or branched-C₁₋₆ alkoxy, straight-         or branched-C₁₋₆ alkoxycarbonyl, amino, straight- or         branched-C₁₋₆ alkanoylamino, phenyl-(CH₂)_(q)-carbonylamino         (wherein q represents an integer selected from 0 to 6),         straight- or branched-C₁₋₆ alkylbenzoylamino,         naphthylcarbonylamino, thenoylamino, nitro, cyano, carboxy,         straight- or branched-C₁₋₆ alkyl sulfonyl, oxazolidinonyl, or         substituents represented by the formula, —SO₂—NR⁵¹R⁵², or         —CO—NR⁵¹R⁵²,     -   wherein     -   R⁵¹ and R⁵² are independently selected from the group consisting         of hydrogen, straight- or branched-C₁₋₆ alkyl optionally         substituted by cyano or carbamoyl and tetrazolyl optionally         substituted by C₁₋₆ alkylnitrile, or     -   R⁵¹ and R⁵² may form, together with the adjacent N, a saturated         5 to 8 membered ring optionally interrupted by NH,     -   R⁶ represents hydrogen, halogen, straight or branched C₁₋₆ alkyl         optionally substituted by mono di or tri halogen, or straight or         branched C₁₋₆ alkoxy, or     -   R⁵ and R⁶ may form a pyrrol ring fused to adjacent phenyl, or         pyridine; and     -   R⁷ represents

-   -   wherein     -   n represents an integer selected from 1 to 3, m represents an         integer selected from 0 to 3,     -   R⁷¹ is hydrogen, C₃₋₈ cycloalkyl optionally interrupted by NH,         N—CH₃ or O, straight- or branched C₁₋₆ allkoxycarbonyl, phenyl         optionally substituted by straight- or branched C₁₋₆ alkyl,         benzyl, formyl, or     -    straight- or branched C₁₋₆ alkyl         -   wherein the alkyl is optionally substituted by hydroxy,             straight- or branched-C₁₋₆ alkoxy, hydroxy straight- or             branched-C₁₋₆ alkoxy, carboxy, straight- or branched-C₁₋₆             alkoxycarbonyl, straight- or branched-C₁₋₆ alkylthio,             di(straight- or branched-C₁₋₆ alkyl)amino, mono, di or tri             halogen, or C₃₋₈ cycloalkyl optionally interrupted by NH or             O,     -   R⁷¹¹ and R⁷¹² are independently selected from the group         consisting of hydrogen, halogen, hydroxy, carboxy, cyano,         straight-or branched C₁₋₆ alkyl optionally substituted by         hydroxy, carboxy, or mono, di or tri halogen, carbamoyl, di         (straight-or branched C₁₋₆ alkyl)amino carbonyl, and         —NR^(711a)R^(711b)         -   wherein         -   R^(711a) and R^(711b) are independently selected from the             group consisting of hydrogen, straight- or branched-C₁₋₆             alkyl, straight- or branched-C₁₋₆ alkanoyl, and straight- or             branched-C₁₋₆ alkylsulfonyl, or         -   R⁷¹ and R⁷¹¹ may form, together with the adjacent N atom, a             5 to 8 membered saturated ring;         -   R⁷² is hydrogen, or straight- or branched-C₁₋₆ alkyl;         -   R⁷³ is hydrogen, or straight- or branched-C₁₋₆ alkyl,         -   R⁷⁴ is hydrogen, or straight- or branched-C₁₋₆ alkyl             optionally substituted by phenyl, or         -   R⁷³ and R⁷⁴ may form, together with adjacent N atom, a 5 to             8 membered saturated ring optionally substituted by C₁₋₆             alkyl and optionally interrupted by NH or O;         -   R⁷⁵ is straight- or branched-C₁₋₆ alkylene or a 3 to 8             membered saturated or unsaturated ring;         -   p represents an integer selected from 0 to 4;         -   A ring represents a 3 to 8 membered saturated ring, in which             the nitrogen atom N^(A) is the only hetero atom;         -   B ring represents a 3 to 8 membered saturated ring, in which             the nitrogen atom N^(B) is the only hetero atom; and         -   C ring and D ring together form a 7 to 12 membered             diazabicyclic ring.

A 7 to 12 membered diazabicyclic ring stands for a saturated bicyclic ring system consisting of 5 to 10 carbon atoms and 1 to 2 nitrogen atoms, wherein said bicyclic ring system does not exhibit a spiro ring connection. Preferred are 8 to 10 membered ring systems.

This invention is also to provide a method for treating or preventing a CCR3 related disorder or disease in a human or animal subject, comprising administering to said subject a therapeutically effective amount of the sulfonamide derivative shown in the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof.

Further this invention is to provide a use of the sulfonamide derivative shown in the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof in the preparation of a medicament for treating or preventing a CCR3 related disorder or disease.

The compounds of the present invention surprisingly show excellent CCR3 antagonistic activity. They are, therefore suitable for the production of medicament or medical composition, which may be useful to treat CCR3 related diseases.

More specifically, since the compounds of the present invention antagonise CCR3, they are useful for treatment and prophylaxis of diseases as follows:

asthma, rhinitis, and allergic diseases, and autoimmune pathologies such as rheumatoid arthritis, Grave's disease, and atherosclerosis.

Therefore, CCR3 is an important target and antagonism of CCR3 is likely to be effective in the treatment and prophylaxis of such inflammatory and immunoregulatory disorders and diseases.

The compounds of the present invention are also useful for treatment and prophylaxis of diseases like virus infections including HIV, lung granuloma, and Alzheimer's diseases, since the diseases also relate to CCR3.

In another embodiment, the compounds of formula (I) are those wherein:

-   X, Y, Z¹, Z², R¹, R², R³, R⁴, R⁰ and R⁷ are as defined above, -   R⁵ is chloro, iodo, nitro, or cyano, and -   R⁶ is hydrogen.

In another embodiment, the compounds of formula (I) are those wherein:

-   X, Y, Z¹ and Z² are as defined above, -   R¹ is halogen, or straight- or branched-C₁₋₆ alkyl optionally     substituted by mono, di or tri halogen; -   R² is halogen, or straight- or branched-C₁₋₆ alkyl optionally     substituted by mono, di or tri halogen; -   R³ is hydrogen; -   R⁴ is hydrogen; -   R⁰ is hydrogen; -   R⁵ is halogen, nitro, or cyano; -   R⁶ is hydrogen; and -   R⁷ represents

-   wherein -   n represents an integer selected from 1 to 3, m represents an     integer selected from 0 to 3, -   R⁷¹ is hydrogen, straight- or branched C₁₋₆ alkyl optionally     substituted by hydroxy or hydroxy straight- or branched-C₁₋₆ alkoxy,     C₃₋₈ cycloalkyl, straight- or branched C₁₋₆ alkoxycarbonyl, phenyl     optionally substituted by straight- or branched C₁₋₆ alkyl, benzyl,     or formyl, -   R⁷¹¹ and R⁷¹² are independently selected from the group consisting     of hydrogen, halogen, carboxy, or straighter branched C₁₋₆ alkyl, or -   R⁷¹ and R⁷¹¹ may form, together with the adjacent N atom, a 5 to 8     membered saturated ring; -   R⁷² is hydrogen, or straight- or branched-C₁₋₆ alkyl, -   R⁷³ is hydrogen, or straight- or branched-C₁₋₆ alkyl, -   R⁷⁴ is hydrogen, or straight- or branched-C₁₋₆ alkyl, or -   R⁷³ and R⁷⁴ may form, together with adjacent N atom, a 5 to 8     membered saturated ring optionally interrupted by NH or O; -   R⁷⁵ is straight- or branched-C₁₋₆ alkylene or a 3 to 8 membered     saturated or unsaturated ring; -   p represents an integer selected from 0 to 4; -   A ring represents a 3 to 8 membered saturated ring, in which the     nitrogen atom N^(A) is the only hetero atom; -   B ring represents a 3 to 8 membered saturated ring, in which the     nitrogen atom N^(B) is the only hetero atom; and -   C ring and D ring together form a 7 to 12 membered diazabicyclic     ring.

In another embodiment, the compounds of formula (I) are those wherein:

-   X, Y, Z¹ and Z² are as defined above, -   R¹ and R² are identical or different and represent chloro, or     methyl; -   R³ is hydrogen or fluoro; -   R⁴ is hydrogen; -   R⁰ is hydrogen; -   R⁵ is chloro, iodo, nitro, or cyano; -   R⁶ is hydrogen; and -   R⁷ represents

-   -   wherein         -   n represents an integer selected from 1 to 3, m represents             an integer selected from 0 to 3,         -   R⁷¹ is hydrogen, straight- or branched C₁alkyl optionally             substituted by hydroxy or hydroxy straight- or branched-C₁₋₆             alkoxy, C₃₋₈ cycloalkl, straight- or branched C₁₋₆             alkoxycarbonyl, phenyl optionally substituted by straight-             or branched C₁₋₆ alkyl, benzyl, or formyl,         -   R⁷¹¹ and R⁷¹² are independently selected from the group             consisting of hydrogen, halogen, carboxy, or straight-or             branched C₁₋₆ alkyl, or         -   R⁷¹ and R⁷¹¹ may form, together with the adjacent N atom, a             5 to 8 membered saturated ring;         -   R⁷² is hydrogen, or straight- or branched-C₁₋₆ alkyl;         -   R⁷³ is hydrogen, or straight- or branched-C₁₋₆ alkyl,         -   R⁷⁴ is hydrogen, or straight- or branched-C₁₋₆ alkyl, or         -   R⁷³ and R⁷⁴ may form, together with adjacent N atom, a 5 to             8 membered saturated ring optionally interrupted by NH or O;         -   R⁷⁵ is straight- or branched-C₁₋₆ alkylene or a 3 to 8             membered saturated or unsaturated ring;         -   p represents an integer selected from 0 to 4;         -   A ring represents a 3 to 8 membered saturated ring, in which             the nitrogen atom N^(A) is the only hetero atom;         -   B ring represents a 3 to 8 membered saturated ring, in which             the nitrogen atom N^(B) is the only hetero atom; and         -   C ring and D ring together form a 7 to 12 membered             diazabicyclic ring.

In another embodiment, the compounds of formula (I) are those wherein:

-   X, Y, Z¹ and Z² are as defined above, -   R¹ is hydrogen, fluoro, chloro, bromo, methyl, isopropyl, butyl,     tert-butyl, trifluoromethyl, methoxy, amino, dimethylamino, acetyl,     or nitro; -   R² is hydrogen, fluoro, chloro, methyl, isopropyl, tert-butyl,     trifluoromethyl, methoxy, or cyano; -   R³ is hydrogen or fluoro; -   R⁴ is hydrogen; -   R⁰ is hydrogen; -   R⁵ is chloro, iodo, nitro, or cyano; -   R⁶ is hydrogen; and -   R⁷ represents

-   -   wherein     -   n represents an integer 1,     -   m represents an integer selected from 1 or 2,     -   R⁷¹ represents hydrogen, methyl, ethyl or isopropyl;     -   R⁷¹¹ represents hydrogen, methyl, or carboxy     -   R⁷¹² represents hydrogen or methyl, or     -   R⁷¹ and R⁷¹¹ may form, together with the adjacent N atom, a 5         membered saturated ring;     -   R⁷² is hydrogen, methyl, or ethyl;     -   R⁷³ is hydrogen, or methyl,     -   R⁷⁴ is hydrogen, methyl, or ethyl, or     -   R⁷³ and R⁷⁴ may form, together with adjacent N atom, piperidino,         morpholino, or pyrrolidino;     -   R⁷⁵ is phenyl;     -   p represents an integer selected from 0 to 4;     -   A ring represents piperidino, or pyrrolidino;     -   B ring represents pyrrolidino; and     -   C ring and D ring together form a 7 to 12 membered diazabicyclic         ring.

Yet other preferred compounds of formula (I) represent formula (I-2) and are those

wherein

-   R¹ is hydrogen, halogen, straight- or branched-C₁₋₆ alkyl optionally     substituted by mono, di or tri halogen, straight- or branched-C₁₋₆     alkoxy, straight- or branched-C₁₋₆ alkoxy carbonyl, amino, straight-     or branched-C₁₋₆ alkylamino, di(straight- or branched-C₁₋₆     alkyl)amino, straight- or branched-C₁₋₆ alkanoyl, or nitro, -   R² is hydrogen, halogen, straight- or branched-C₁₋₆ alkyl optionally     substituted by mono, di or tri halogen, straight- or branched-C₁₋₆     alkoxy, or cyano, or -   R¹ and R² may form benzene ring or C₃₋₈ cycloalkyl fused to the     adjacent phenyl; -   R³ is hydrogen or halogen, -   Y represents O, NH, NCH₃, S, S(O), or SO₂; -   R⁵ is hydrogen, halogen, hydroxy, straight- or branched-C₁₋₆ alkyl     optionally substituted by mono, di, or tri halogen or hydroxy,     straight- or branched-C₁₋₆ alkoxy, straight- or branched-C₁₋₆     alkoxycarbonyl, amino, straight- or branched-C₁₋₆ alkanoylamino,     phenyl-(CH₂)_(q)-carbonylamino (wherein q represents an integer     selected from 0 to 6), straight- or branched-C₁₋₆ alkylbenzoylamino,     naphthylcarbonylamino, thenoylamino, nitro, cyano, carboxy,     straight- or branched-C₁₋₆ alkyl sulfonyl, oxazolidinonyl, or     substituents represented by the formula, —SO₂—NR⁵¹R⁵², or     —CO—NR⁵¹R⁵²,     -   wherein     -   R⁵¹ and R⁵² are identical or different and represent hydrogen,         straight- or branched-C₁₋₆ alkyl optionally substituted by cyano         or carbamoyl, tetrazolyl optionally substituted by C₁₋₆         alkylnitrile, or R⁵¹ and R⁵² may form, together with the         adjacent N, a saturated 5 to 8 membered ring optionally         interrupted by NH,     -   R⁶ is hydrogen, halogen, straight or branched C₁₋₆ alkyl         optionally substituted by mono, di or tri halogen, or straight         or branched C₁₋₆ alkoxy, or     -   R⁵ and R⁶ may form a pyrrol ring fused to adjacent phenyl; and     -   R⁷ represents

-   -   -   wherein         -   n represents an integer selected from 1 to 3, m represents             an integer selected from 0 to 3,         -   R⁷¹ is hydrogen, straight- or branched C₁₋₆ alkyl optionally             substituted by hydroxy or hydroxy straight- or branched-C₁₋₆             alkoxy, C₃₋₈ cycloalkyl, straight- or branched C₁₋₆             alkoxycarbonyl, phenyl optionally substituted by straight-             or branched C₁₋₆ alkyl, benzyl, or formyl,         -   R⁷¹¹ and R⁷¹² are independently selected from the group             consisting of hydrogen, halogen, hydroxy, carboxy, cyano,             straight-or branched C₁₋₆ alkyl optionally substituted by             hydroxy, carboxy, or mono, di or tri halogen, carbamoyl, di             (straight-or branched C₁₋₆ alkyl)amino carbonyl, or             —NR^(711a)R^(711b)             -   wherein             -   R^(711a) and R^(711b) are independently selected from                 the group consisting of hydrogen, straight- or                 branched-C₁₋₆ alkyl, straight- or branched-C₁₋₆                 alkanoyl, or straight- or branched-C₁₋₆ alkylsulfonyl,                 or             -   R⁷¹ and R⁷¹¹ may form, together with the adjacent N                 atom, a 5 to 8 membered saturated ring;             -   R⁷² is hydrogen, or straight- or branched-C₁₋₆ alkyl;             -   R⁷³ is hydrogen, or straight- or branched-C₁₋₆ alkyl,             -   R⁷⁴ is hydrogen, or straight- or branched-C₁₋₆ alkyl, or             -   R⁷³ and R⁷⁴ may form, together with adjacent N atom, a 5                 to 8 membered saturated ring optionally interrupted by                 NH or O;             -   R⁷⁵ is straight- or branched-C₁₋₆ alkylene or a 3 to 8                 membered saturated or unsaturated ring;             -   p represents an integer selected from 0 to 4;             -   A ring represents a 3 to 8 membered saturated ring, in                 which the nitrogen atom N^(A) is the only hetero atom;             -   B ring represents a 3 to 8 membered saturated ring, in                 which the nitrogen atom N^(B) is the only hetero atom;                 and             -   C ring and D ring together form a 7 to 12 membered                 diazabicyclic ring.

Yet other preferred compounds of formula (I-2) are those wherein:

-   R¹ is hydrogen, halogen, straight- or branched-C₁₋₆ allyl optionally     substituted by mono, di or tri halogen, straight- or branched-C₁₋₆     alkoxy, straight- or branched-C₁₋₆ alkoxy carbonyl, amino, straight-     or branched-C₁₋₆ alkylamino, di(straight- or branched-C₁₋₆     alkyl)amino, straight- or branched-C₁₋₆ alkanoyl, or nitro, -   R² is hydrogen, halogen, straight- or branched-C₁₋₆ alkyl optionally     substituted by mono, di or tri halogen, straight- or branched-C₁₋₆     alkoxy, or cyano, or -   R¹ and R² may form benzene ring or C₅₋₈ cycloalkyl fused to the     adjacent phenyl; -   R³ is hydrogen or halogen, -   Y represents O, NH, NCH₃, S, S(O), or SO₂; -   R⁵ is chloro, iodo, nitro, or cyano; -   R⁶ is hydrogen; and -   R⁷ represents

-   wherein -   n represents an integer selected from 1 to 3, m represents an     integer selected from 0 to 3, -   R⁷¹ is hydrogen, straight- or branched C₁₋₆ alkyl optionally     substituted by hydroxy or hydroxy straight- or branched-C₁₋₆ alkoxy,     C₃₋₈ cycloalkyl, straight- or branched C₁₋₆ alkoxycarbonyl, phenyl     optionally substituted by straight- or branched C₁₋₆ alkyl, benzyl,     or formyl, -   R⁷¹¹ and R⁷¹² are independently selected from the group consisting     of hydrogen, halogen, carboxy, or straight-or branched C₁₋₆ alkyl,     or -   R⁷¹ and R⁷¹¹ may form, together with the adjacent N atom, a 5 to 8     membered saturated ring; -   R⁷² is hydrogen, or straight- or branched-C₁₋₆ alkyl; -   R⁷³ is hydrogen, or straight- or branched-C₁₋₆ alkyl, -   R⁷⁴ is hydrogen, or straight- or branched-C₁₋₆ alky, or -   R⁷³ and R⁷⁴ may form, together with adjacent N atom, a 5 to 8     membered saturated ring optionally interrupted by NH or O; -   R⁷⁵ is straight- or branched-C₁₋₆ alkylene or a 3 to 8 membered     saturated or unsaturated ring; -   p represents an integer selected from 0 to 4; -   A ring represents a 3 to 8 membered saturated ring, in which the     nitrogen atom N^(A) is the only hetero atom; -   B ring represents a 3 to 8 membered saturated ring, in which the     nitrogen atom N^(B) is the only hetero atom; and -   C ring and D ring together form a 7 to 12 membered diazabicyclic     ring.

In another embodiment, the compounds of formula (I-2) are those wherein:

-   R¹ is hydrogen, halogen, or straight- or branched-C₁₋₆ alkyl     optionally substituted by mono, di or tri halogen; -   R² is hydrogen, halogen, or straight- or branched-C₁₋₆ alkyl     optionally substituted by mono, di or tri halogen; -   R³ is hydrogen or halogen, -   Y is O, NH, NCH₃, S, S(O), or SO₂; -   R⁵ is halogen, nitro, or cyano; -   R⁶ is hydrogen; and -   R⁷ represents

-   -   wherein         -   n represents an integer selected from 1 to 3,         -   m represents an integer selected from 0 to 3,         -   R⁷¹ is hydrogen, straight- or branched C₁₋₆ alkyl optionally             substituted by hydroxy or hydroxy straight- or branched-C₁₋₆             alkoxy, C₃₋₈ cycloalkyl, straight- or branched C₁₋₆             alkoxycarbonyl, phenyl optionally substituted by straight-             or branched C₁₋₆ alkyl, benzyl, or formyl,         -   R⁷¹¹ represents hydrogen, methyl, or carboxy,         -   R⁷¹² represents hydrogen or methyl, or         -   R⁷¹ and R⁷¹¹ may form, together with the adjacent N atom, a             5 to 8 membered saturated ring;         -   R⁷² is hydrogen, or straight- or branched-C₁₋₆ alkyl;         -   R⁷³ is hydrogen, or straight- or branched-C₁₋₆ alkyl,         -   R⁷⁴ is hydrogen, or straight- or branched-C₁₋₆ alkyl, or         -   R⁷³ and R⁷⁴ may form, together with adjacent N atom, a 5 to             8 membered saturated ring optionally interrupted by NH or O;         -   R⁷⁵ is straight- or branched-C₁ alkylene or a 3 to 8             membered saturated or unsaturated ring;         -   p represents an integer selected from 0 to 4;         -   A ring represents a 3 to 8 membered saturated ring, in which             the nitrogen atom N^(A) is the only hetero atom;         -   B ring represents a 3 to 8 membered saturated ring, in which             the nitrogen atom N^(B) is the only hetero atom; and         -   C ring and D ring together form a 7 to 12 membered             diazabicyclic ring.

In another embodiment, the compounds of formula (I-2) are those wherein:

-   R¹, R² and R³ are identical or different and represent hydrogen,     chloro, or methyl; -   Y is O, NH, NCH₃, S, S(O), or SO₂; -   R⁵ is chloro, iodo, nitro, or cyano; -   R⁶ is hydrogen; and -   R⁷ represents

-   -   wherein     -   n represents an integer selected from 1 to 3,     -   m represents an integer selected from 1 to 3,     -   R⁷¹ is hydrogen, straight- or branched C₁₋₆ alkyl optionally         substituted by hydroxy or hydroxy straight- or branched-C₁₋₆         alkoxy, C₃₋₈ cycloalkyl, straight- or branched C₁alkoxycarbonyl,         phenyl optionally substituted by straight- or branched C₁₋₆         alkyl, benzyl, or formyl,     -   R⁷¹¹ represents hydrogen, methyl, or carboxy or     -   R⁷¹ and R⁷¹¹ may form, together with the adjacent N atom, a 5 to         8 membered saturated ring;     -   R⁷² is hydrogen, or straight- or branched-C₁₋₆ alkyl;     -   R⁷³ is hydrogen, or straight- or branched-C₁₋₆ alkyl;     -   R⁷⁴ is hydrogen, or straight- or branched-C₁₋₆ alkyl; or     -   R⁷³ and R⁷⁴ may form, together with adjacent N atom, a 5 to 8         membered saturated ring optionally interrupted by NH or O;     -   R⁷⁵ is straight- or branched-C₁₋₆ alkylene or a 3 to 8 membered         saturated or unsaturated ring;     -   p represents an integer selected from 0 to 4;     -   A ring represents a 3 to 8 membered saturated ring, in which the         nitrogen atom N^(A) is the only hetero atom;     -   B ring represents a 3 to 8 membered saturated ring, in which the         nitrogen atom N^(B) is the only hetero atom; and     -   C ring and D ring together form a 7 to 12 membered diazabicyclic         ring.

In another embodiment, the compounds of formula (I-2) are those wherein

-   R¹ is halogen, or straight- or branched-C₁₋₆ alkyl optionally     substituted by mono, di or tri halogen; -   R² is halogen, or straight- or branched-C₁₋₆ alkyl optionally     substituted by mono, di or tri halogen; -   R³ is hydrogen or fluoro; -   Y is O, NH, NCH₃, S, S(O), or SO₂; -   R⁵ is hydrogen, fluoro, chloro, bromo, iodo, trifluoromethyl,     hydroxy, methoxy, amino, acetylamino, isobutylcarbonylamino,     tert-butylcarbonylamino, benzoylamino, benzylcarbonylamino,     phenethylcarbonylamino, methylbenzoylamino, naphthylcarbonylamino,     thenoylamino, nitro, cyano, methylsulfonyl, dimethyaminosulfonyl,     piperazinosulfonyl, dimethyaminocarbonyl, or piperazinocarbonyl; -   R⁶ is hydrogen, methyl, or methoxy; or -   R⁵ and R⁶ may form a pyrrol ring fused to adjacent phenyl; and -   R⁷ represents

-   -   wherein     -   n represents an integer 1,     -   m represents an integer 1 or 2,     -   R⁷¹ is hydrogen, methyl, ethyl, isopropyl, sec-butyl, branched         pentyl, hydroxyethyl, hydroxyethoxyethyl, cyclopentyl,         cyclohexyl, tert-butoxycarbonyl, phenyl, tolyl, benzyl, or         formyl,     -   R⁷¹¹ represents hydrogen, methyl, or carboxy,     -   R⁷¹² represents hydrogen or methyl, or     -   R⁷¹ and R⁷¹¹ may form, together with the adjacent N atom, a 5         membered saturated ring;     -   R⁷² is hydrogen, methyl, or ethyl;     -   R⁷³ is hydrogen, or methyl,     -   R⁷⁴ is hydrogen, methyl, or ethyl, or     -   R⁷³ and R⁷⁴ may form, together with adjacent N atom, piperidino,         morpholino, or pyrrolidino;     -   R⁷⁵ is phenyl;     -   p represents an integer selected from 0 to 4;     -   A ring represents piperidino, or pyrrolidino;     -   B ring represents pyrrolidino; and

C ring and D ring together form a 7 to 12 membered diazabicyclic ring.

In another embodiment, the compounds of formula (I-2) are those wherein;

-   R¹ is hydrogen, fluoro, chloro, bromo, methyl, isopropyl, butyl,     tert-butyl, trifluoromethyl, methoxy, amino, dimethylamino, acetyl,     or nitro; -   R² is hydrogen, fluoro, chloro, methyl, isopropyl, tert-butyl,     trifluoromethyl, methoxy, or cyano; -   R³ is hydrogen or fluoro; -   Y is O, NH, NCH₃, S, S(O), or SO₂; -   R⁵ is hydrogen, fluoro, chloro, bromo, iodo, trifluoromethyl,     hydroxy, methoxy, amino, acetylamino, isobutylcarbonylamino,     tert-butylcarbonylamino, benzoylamino, benzylcarbonylamino,     phenethylcarbonylamino, methylbenzoylamino, naphthylcarbonylamino,     thenoylamino, nitro, cyano, methylsulfonyl, dimethylaminosulfonyl,     piperazinosulfonyl, dimethylaminocarbonyl, or piperazinocarbonyl; -   R⁶ is hydrogen, methyl, or methoxy; or -   R⁵ and R⁶ may form a pyrrol ring fused to adjacent phenyl, and -   R⁷ represents

-   -   wherein     -   n represents an integer 1,     -   m represents an integer 1 or 2,         -   R⁷¹ represents hydrogen, methyl, ethyl, isopropyl,             sec-butyl, branched pentyl, hydroxyethyl,             hydroxyethoxyethyl, cyclopentyl, cyclohexyl,             tert-butoxycarbonyl, phenyl, tolyl, benzyl, or formyl,         -   R⁷¹¹ represents hydrogen, methyl, or carboxy         -   R⁷¹² represents hydrogen or methyl, or         -   R⁷¹ and R⁷¹¹ may form, together with the adjacent N atom, a             5 membered saturated ring;         -   R⁷² is hydrogen, methyl, or ethyl,         -   R⁷³ is hydrogen, or methyl,         -   R⁷⁴ is hydrogen, methyl, or ethyl, or         -   R⁷³ and R⁷⁴ may form, together with adjacent N atom,             piperidino, morpholino, or pyrrolidino;         -   R⁷⁵ is phenyl;         -   p represents an integer selected from 0 to 4;         -   A ring represents piperidino, or pyrrolidino;         -   B ring represents pyrrolidino; and         -   C ring and D ring together form a 7 to 12 membered             diazabicyclic ring.

In another embodiment, the compounds of formula (I-2) are those wherein;

-   R¹ is chloro, bromo, or methyl; -   R² is hydrogen, chloro, bromo, or methyl; -   R³ is hydrogen or fluoro; -   Y represents O, S, or S(O); -   R⁵ represents hydrogen, chloro, nitro, or cyano; -   R⁶ represents hydrogen; -   R⁷ represents

-   -   wherein     -   R⁷¹ represents hydrogen, methyl, ethyl or isopropyl;     -   R⁷¹¹ represents hydrogen, methyl, or carboxy;     -   R⁷¹² represents hydrogen or methyl;     -   R⁷² is hydrogen, methyl, or ethyl;     -   R⁷³ is hydrogen, methyl, or ethyl;     -   R⁷⁴ is hydrogen, methyl, or ethyl; or     -   R⁷³ and R⁷⁴ may form, together with adjacent N atom, piperidino,         or pyrrolidino,     -   R⁷⁵ is phenyl;     -   p represents integer 0 or 1;     -   A ring represents piperidino, or pyrrolidino; and     -   B ring represents pyrrolidino.

The preferable compounds of the present invention are as follows:

-   1-{[2-(3,5-dimethylphenoxy)-5-nitrophenyl]sulfonyl}-4-ethylpiperazine, -   1-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}piperazine, -   1-{[2-(3,5-dimethylphenoxy)-5-nitrophenyl]sulfonyl}-4-isopropylpiperazine, -   4-(3,5-dimethylphenoxy)-3-(1-piperazinylsulfonyl)benzonitrile, -   1-{[5-chloro-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-4-ethylpiperazine, -   1-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-4-(1-pyrrolidinyl)piperidine, -   4-(3,5-dichlorophenoxy)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]sulfonyl}benzonitrile, -   4-(3,5-dichlorophenoxy)-3-(1-piperazinylsulfonyl)benzonitrile, -   1-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-N,N-diethyl-3-pyrrolidinamine, -   (2S)-1-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl)-2-(1-pyrrolidinylmethyl)pylolidine, -   3-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-ylsulfonyl]-4-(3,5-dichlorophenoxy)benzonitrile, -   4-[(3,5-dichlorophenyl)sulfanyl]-3-(1-piperazinylsulfonyl)     benzonitrile, -   4-[(3,5-dichlorophenyl)sulfinyl]-3-(1-piperazinylsulfonyl)     benzonitrile, -   1-{[2-(3,5-dibromophenoxy)-5-nitrophenyl]sulfonyl}piperazine, -   1-{[2-(3,5-dichloro-2-fluorophenoxy)-5-nitropbenyl]sulfonyl}piperazine, -   1-{[5-cyano-2-(3,5-dichlorophenoxy)phenyl]sulfonyl}-2-piperazinecarboxylic     acid, -   1-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-2-piperazinecarboxylic     acid, -   1-{[2-(3,5-dimethylphenoxy)-5-nitrophenyl]sulfonyl}-1,4-diazepane, -   1-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-1,4-diazepane, -   1-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-3,5-dimethylpiperazine, -   3-(1,4-diazepan-1-ylsulfonyl)-4-(3,5-dichlorophenoxy) benzonitrile, -   1′-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-1,3′-bipyrrolidine, -   3-(1,3′-bipyrrolidin-1′-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile, -   1-({2-[(3,5-dichlorophenyl)sulfanyl]-5-nitrophenyl}sulfonyl)-4-(1-pyrrolidinyl)piperidine, -   4-(3,5-dichlorophenoxy)-3-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylsulfonyl)benzonitrile,     and -   3-(1,4-diazepan-1-ylsulfonyl)-4-[(3,5-dichlorophenyl)sulfanyl]benzonitrile,     and their tautomeric and stereoisomeric form, and physiologically     acceptable salts thereof.

The compound of the formula (I) of the present invention can be prepared by combining various known methods. In some embodiments, one or more of the substituents, such as amino group, carboxyl group, and hydroxyl group of the compounds used as starting materials or intermediates are advantageously protected by a protecting group known to those skilled in the art. Examples of the protecting groups are described in “Protective Groups in Organic Synthesis (3rd Edition)” by Greene and Wuts, John Wiley and Sons, New York 1999.

The compound represented by the general formula (I-a) can be prepared by the Reaction A or A′ below.

-   -   wherein     -   X, Z¹, Z² and R⁶ are as defined above, Y′ is O, NH, or S, R⁵′ is         nitro, C₁₋₆ alkyl, C₁₋₆ alkylsulfonyl, carboxy and R⁷′ is the         same as R⁷ as defined above or protected R⁷.

Compound 1 (wherein L and L′ are identical or different and represent leaving group, such as halogen atom e.g., fluorine, chlorine, bromine, or iodine atom; C₆₋₁₀ arylsulfonyloxy group e.g., benzenesulfonyloxy, or p-toluenesulfonyloxy, and C₁₋₄ alkylsulfonyloxy group, e.g., trifluoromethanesulfonyloxy, methanesulfonyloxy and the like) and H—R⁷′ can be reacted to obtain compound 2 in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; nitrites such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about −10° C. to 200° C., and preferably about 10° C. to 80° C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 hr to 24 hrs.

The reaction can be advantageously conducted in the presence of a base. The examples of the base include an alkali metal hydride such as sodium hydride or potassium hydride; alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.

Then compound 2 and HY′—X (wherein X and Y′ are the same as defined above) can be reacted in a similar manner as that of the reaction of A-1 and H—R⁷′ to obtain the compound (I-a).

Compound 3 (wherein L is identical or different and represent leaving group, such as halogen atom e.g., fluorine, chlorine, bromine, or iodine atom; C₆₋₁₀ arylsulfonyloxy group e.g., benzenesulfonyloxy, or p-toluenesulfonyloxy; and C₁₋₄ alkylsulfonyloxy group, e.g., trifluoromethanesulfonyloxy, methanesulfonyloxy and the like, W represents nitro, halogen, thiol, C₁₋₆ alkyl sulfinyl, sulfinic acid, sulfinic acid, sulfonamide and the like) and HY′—X can be reacted to obtain compound 4 in a similar manner as that for the preparation of I-a from compound 2 and HY′—X.

Compound 4 can be converted to compound 5 (wherein L′ is as defined above) by known method in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO); organic acid such as acetic acid; inorganic acid such as HCl and H₂SO₄; water and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to about −10° C. to 200° C., and preferably about 10° C. to 80° C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.

Then compound 5 and H—R⁷′ can be reacted to obtain (I-a) in a similar manner as that for the preparation of compound 2 from compound 1 and H—R⁷′.

The compound (I-a) can be further reacted to modify R⁷′, e.g. to deprotect, or to modify R⁵′ to obtain the compound having amino, halogen, hydroxy, cyano, C₁₋₆ alkoxy or amide group.

Alternatively, the compound represented by the general formula (I-b) can be prepared by the Reaction B below.

-   -   wherein     -   X, Z¹ and Z² are as defined above, R⁵′ is halogen, carboxy or         nitro and R⁷′ is the same as R⁷ as defined above or protected         R⁷.

Reaction B is especially advantageous when R⁵″ is Br.

First, compound 6 and sulfonic acid halide (e.g., chlorosulfonic acid) or equivalent thereof can be reacted to obtain compound 7 (wherein L′ is as defined above) in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide (DMSO), and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to, about −10° C. to 200° C., and preferably about 10° C. to 80° C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.

Compound 8 can be prepared from compound 7 in two steps; (step 1) the reaction with H—R⁷′ and (step 2) deprotection of methoxy group. (step 1) The reaction of compound 7 and H—R⁷′ can be performed in a similar manner as that for the preparation of compound 2 from compound 1 and H—R⁷′.

(Step 2) The successive deprotection of methoxy group to obtain B-3 can be done by the reaction with Lewis acid such as, for example, BBr₃, in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; nitrites such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to about −10° C. to 200° C., and preferably about 10° C. to 80° C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.

Then compound 8 can be reacted with X-L″ (wherein X is defined as above, L″ represents leaving group, such as boronic acid, halogen atom e.g., fluorine, chlorine, bromine, or iodine atom) to obtain the compound (I-b). The reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitrites such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to about −10° C. to 200° C., and preferably about 10° C. to 100° C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs. The reaction can be carried out in the presence of a catalyst, including for instance, cooper salts such as cooper(II) acetate, palladium salts such as palladium (II) acetate, and others. The reaction can be advantageously conducted in the presence of a base. The examples of the base include an alkali metal alkoxide such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; carbonates such as cesium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.

The compound (I-b) can be farther reacted to modify R⁷′, e.g. to deprotect, or to modify R⁵″ to obtain the compound having amino, halogen, hydroxy, cyano, C₁₋₆ alkoxy or amide group.

The compound (I-c) below can be advantageously prepared by the Reaction C below.

-   -   wherein     -   X, Z¹, Z² and R⁵″ are as defined above, Y″ is NH or S, and R⁷′         is the same as R⁷ as defined above or protected R⁷.

First, compound 8, which can be prepared as described in the Reaction B can be reacted with either trifluoromethanesulfonic anhydride or trifluoromethanesulfonic chloride to obtain compound 9. The reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to about −10° C. to 200° C., and preferably about 0° C. to 100° C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs. The reaction can be advantageously conducted in the presence of a base. The examples of the base include organic amines such as pyridine, triethylamine and N,N-diisopropylethylamine, and others.

Then compound 9 and HY″—X can be reacted to obtain compound (I-c) in a similar manner as that for I-a from compound 2 and HY′—X.

The compound (I-c) can be further reacted to modify R⁷′, e.g. to deprotect, or to modif R⁵″ to obtain the compound having amino, halogen, hydroxy, cyano, C₁₋₆ alkoxy or amide group.

The compound (I-d) below can be prepared by the Reaction D below.

-   -   wherein     -   X, Z¹, Z², R⁵ and R⁶ are as defined above, Y′″ is SO or SO₂ and         R⁷′ is the same as R⁷ as defined above or protected R⁷.

The sulfoxide compounds of the formula (I-d′) can be prepared by oxidation of compound (I-a′) using appropriate oxidant including but not limited to, peroxide, such as hydrogen peroxide, t-butyl peroxide; peracids such as meta-chloroperbenzoic acid and the like. The reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.

The reaction temperature is usually, but not limited to about −10° C. to 200° C., and preferably about 0° C. to 100° C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.

The sulfone compounds of the formula (I-d″) can be prepared by oxidation of compound (I-a′) with an oxidant such as, for example, sodium periodate (NaIO₄) or sodium hypochlorite (NaOCl) in the presence of catalyst such as, for instance, ruthenium (III) chloride.

The reaction can be performed in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitrites such as acetonitrile; amides such as N,N-dimethylformamide (DMF), N,N-dimethylacetamide and N-methylpyrrolidone; water and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used. The reaction temperature is usually, but not limited to about −10° C. to 200° C., and preferably about 0° C. to 100° C. The reaction may be carried out for, usually, 30 minutes to 48 hrs and preferably 1 to 24 hrs.

The sulfone compounds of the formula (I-d″) can also be prepared by oxidation of compound (I-d′) in a similar manner as that for the oxidation of compound (I-a′).

The compound (I-d′) and (I-d″) can be further reacted to modify R⁷′, e.g., to deprotect, or to modify R⁵′ to obtain the compound having amino, halogen, hydroxy, cyano, C₁₋₆ alkoxy or amide group.

When the compound shown by the formula (I) or a salt thereof has tautomeric isomers and/or stereoisomers (e.g, geometrical isomers and conformational isomers), each of their separated isomer and mixtures are also included in the scope of the present invention.

When the compound shown by the formula (I) or a salt thereof has an asymmetric carbon in the structure, their optically active compounds and racemic mixtures are also included in the scope of the present invention.

Typical salts of the compound shown by the formula (I) include salts prepared by reaction of the compounds of the present invention with a mineral or organic acid, or an organic or inorganic base. Such salts are known as acid addition and base addition salts, respectively.

Acids to form acid addition salts include inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like, and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.

Base addition salts include those derived from inorganic bases, such as, without limitation, ammonium hydroxide, alkaline metal hydroxide, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, tris(hydroxymethyl)aminomethane, and the like. Examples of inorganic bases include, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.

The compound of the present invention or a salts thereof, depending on its substituents, may be modified to form lower alkylesters or known other esters; and/or hydrates or other solvates. Those esters, hydrates, and solvates are included in the scope of the present invention.

The compound of the present invention may be administered in oral forms, such as, without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions. They may also be administered in parenteral forms, such as, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like forms, well-known to those of ordinary skill in the pharmaceutical arts. The compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal delivery systems well-known to those of ordinary skilled in the art.

The dosage regimen with the use of the compounds of the present invention is selected by one of ordinary skill in the arts, in view of a variety of factors, including, without limitation, age, weight, sex, and medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed, the particular compound and salt thereof employed.

The compounds of the present invention are preferably formulated prior to administration together with one or more pharmaceutically-acceptable excipients. Excipients are inert substances such as, without limitation carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material.

Yet another embodiment of the present invention is pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically-acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Pharmaceutical formulations of the invention are prepared by combining a therapeutically effective amount of the compounds of the invention together with one or more pharmaceutically-acceptable excipients therefore. In making the compositions of the present invention, the active ingredient may be mixed with a diluent, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. The carrier may serve as a diluent, which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

For oral administration, the active ingredient may be combined with an oral, and non-toxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose, and the like; together with, optionally, disintegrating agents, such as, without limitation, maize, starch, methyl cellulose, agar bentonite, xanthan gum, alginic acid, and the like; and optionally, binding agents, for example, without limitation, gelatin, acacia, natural sugars, beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc, and the like.

In powder forms, the carrier may be a finely divided solid which is in admixture with the finely divided active ingredient. The active ingredient may be mixed with a carrier having binding properties in suitable proportions and compacted in the shape and size desired to produce tablets. The powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel composition of the present invention. Suitable solid carriers are magnesium carboxymethyl cellulose, low melting waxes, and cocoa butter.

Sterile liquid formulations include suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.

The active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol. Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in suitable oil.

The formulation may be in unit dosage form, which is a physically discrete unit containing a unit dose, suitable for administration in human or other mammals. A unit dosage form can be a capsule or tablets, or a number of capsules or tablets. A “unit dose” is a predetermined quantity of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more excipients. The quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved.

Typical oral dosages of the present invention, when used for the indicated effects, will range from about 0.01 mg/kg/day to about 100 mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day. In the case of parenteral administration, it has generally proven advantageous to administer quantities of about 0.001 to 100 mg/kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or more times per day. Where delivery is via transdermal forms, of course, administration is continuous.

EXAMPLES

The present invention will be described in detail below in the form of examples, but they should by no means be construed as defining the metes and bounds of the present invention.

In the examples below, all quantitative data, if not stated otherwise, relate to percentages by weight.

¹H NMR spectra were recorded using either Bruker DRX-300 (300 MHz for ¹H) spectrometer in CDCl₃. Chemical shifts are reported in parts per million (ppm) with tetramethylsilane (TMS) as an internal standard at zero ppm. Coupling constant (J) are given in hertz and the abbreviations s, d, t, q, m, and br refer to singlet, doublet, triplet, quartet, multiplet, and broad, respectively. Mass spectroscopy data were recorded on a FINNIGAN MAT 95. TLC was performed on a precoated silica gel plate (Merck silica gel 60 F-254). Silica gel (WAKO-gel C-200 (75-150 μm)) was used for all column chromatography separations.

All chemicals were reagent grade and were purchased from Sigma-Aldrich, Wako pure chemical industries, Ltd., Tokyo kasei kogyo Co., Ltd., Nacalai tesque, Inc., Watanabe Chemical Ind. Ltd., Maybridge plc, Lancaster Synthesis Ltd., Merck KgaA, Kanto Chemical Co., Ltd.

The effects of the present compounds were examined by the following assays and pharmacological tests.

[Determination of IC50 Values of Compounds in Receptor Binding Assay]

(1) Cell

-   -   Human CCR3-transformed K562 cells were used. The cloned CCR3         cDNA was constructed with pcDNA3 vector and transfected into a         K562 cell line. The human CCR3-transformed K562 cells were         maintained in RPMI-1640 (Cat.#22400-089, Life Technologies)         supplemented with 10% FCS (Cat.#A-1115-L, Hyclone), 55 μM         2-mercaptoethanol (Cat.#21985-023, Life Technologies), 1 mM         sodium pyruvate (Cat.#11360-070, Life Technologies), 100         units/ml of penicillin G and 100 μg/ml of streptomycin         (Cat.#15140-122, Life Technologies), and 0.4 mg/ml of Geneticin         (Cat.#10131-035, Life Technologies) (hereinafter called “culture         medium”). Before the receptor binding assay, cells were         pretreated with 5 mM sodium butyrate (Cat.#193-01522,         Wako)-containing the culture medium (2×10⁵ cells/ml) for 20-24         hours to increase the expression of CCR3.

(2) Receptor Binding Assay (RBA)

-   -   Butyrate-pretreated cells, suspended in binding buffer (25 mM         HEPES pH 7.6, 1 mM CaCl₂, 5 nM MgCl₂, 0.5% BSA, 0.1% NaN₃) at a         cell density of 2×10⁶ cells/ml, were added into 60 μl/well in         the 96-well round bottom polypropylene plate (Cat.#3365,         Costar). Compounds, diluted with the binding buffer (4-times         higher concentration of the final concentration), were added         into 30 μl/well in the polypropylene plate. [¹²⁵I]-labeled human         eotaxin (Cat.#IM290, Amersham Pharmacia Biotech), diluted with         the binding buffer at the concentration of 0.4 nM (final         concentration; 0.1 nM), was added into 30 μl/well in the         polypropylene plate. Total 120 μl/well of binding reaction         mixture (60 μl/well of cell suspension, 30 μl/well of compound         solution, and 30 μl/well of (¹²⁵I]-labeled eotaxin) were         incubated in the polypropylene plate for 1 hour at room         temperature after the incubation, 100 μl/well of the reaction         mixture was transferred to a filtration plate (Cat.#MAFB-N0B,         Millipore), and washed with the washing buffer (25 mM HEPES pH         7.6, 1 m CaCl₂, 5 mM MgCl₂, 0.5% BSA, 0.1% NaN₃, 0.5 M NaCl)         twice. The 96-well filtration plate was pretreated with 100         μl/well of 0.5% polyethylenimine (Cat.#P-3143, Sigma) for 2-4         hours at room temperature and washed with the washing buffer         twice before use. The non-specific binding was determined by         parallel incubation in the presence of 500 nM of non-labeled         eotaxin (Cat.#23209, Genzyme Techne). The radioactivities         remained on the filter were measured by liquid scintillation         counter (TopCount™, Packard) after an addition of 45 μl/well of         scintillant (Microscint20, Cat.#6013621, Packard). The         inhibition percent at each concentration of compound was         calculated and IC50 values were determined from the inhibition         curve.         [Determination of IC50 Values of Compounds in Calcium         Mobilization assay] (IC₅₀ Ca2+)

(1) Cell

-   -   Human CCR3-transformed K562 cells were used. The human         CCR3-transformed K562 cells were maintained in RPMI-1640         supplemented with 10% FCS, 55 μM 2-mercaptoethanol         (Cat.921985-023, Life Technologies), 1 mM sodium pyruvate, 100         units/ml of penicillin G and 100 μg/ml of streptomycin and 0.4         mg/ml of Geneticin. Before the calcium mobilization assay, cells         were pretreated with 5 mM sodium butyrate-containing the culture         medium (2×10⁵ cells/ml) for 20-24 hours to increase the         expression of CCR3.

(2) Calcium Mobilization Assay

-   -   Butyrate-pretreated cells were loaded with Fluo-3AM         (Cat.#F-1242, Molecular Probes) in loading buffer (Hanks'         solution Cat.#05906 Nissui, 20 mM HEPES pH 7.6, 0.1% BSA, 1 mM         probenecid Cat.#P-8761 Sigma, 1 μM Fluo-3AM, 0.01% pluronic         F-127 Cat.#P-6866 Molecular Probes) at a cell density of 1×10⁷         cells/ml. Then, cells were washed with calcium assay buffer         (Hanks' solution Cat.#05906 Nissui, 20 mM HEPES pH 7.6, 0.1%         BSA, 1 mM Probenecid Cat.#P-8761 Sigma). The cell suspension         (3.3×10⁶ cells/ml) was added into 60 μl/well in the 96-well         clear bottom black plate (Cat.#3904, Costar). Compounds, diluted         (5-times concentration of the final concentration) with the         calcium assay buffer, were added into 20 μl/well in the plate 10         minutes before assay. Human recombinant eotaxin, diluted with         the calcium assay buffer at the concentration of 50 nM (final         concentration; 10 nM), was added into in a polypropylene plate         (Cat.#3365, Costar). Mobilization of cytoplasmic calcium was         measured by FDSS-6000 or FDSS-3000(Hamamatsu Photonics) over 60         sec after the stimulation with 10 nM eotaxin. The inhibition         percent at the each concentration of compound was calculated,         and IC50 values were determined from the inhibition curve.         [Determination of IC50 Values of Compounds in Chemotaxis Assay]

(1) Cell

-   -   Human CCR3-transformed L1.2 cells were used. Human         CCR3-expressing L1.2 stable transformant was established by         electroporation, referring to the methods described in J. Exp.         Med. 183:2437-2448, 1996. The human CCR3-transformed L1.2 cells         were maintained in RPMI-1640 supplemented with 10% FCS, 100         units/ml of penicillin G and 100 μg/ml of streptomycin, and 0.4         mg/ml of Geneticin. One day before the chemotaxis assay, cells         were pretreated with 5 mM sodium butyrate-containing culture         medium (5×10⁵ cells/ml) for 20-24 hours to increase the         expression of CCR3.

(2) Chemotaxis Assay

-   -   Butyrate-pretreated cells were suspended in chemotaxis buffer         (Hanks' solution Cat.#05906 Nissui, 20 mM HEPES pH 7.6, 0.1%         human serum albumin Cat.#A-1887 Sigma) at a cell density of         1.1×10⁷ cells/ml. A mixture of 90 μl of cell suspension and 10         μl of compound solution diluted with chemotaxis buffer (10-times         concentration of the final concentration) were preincubated for         10 minutes at 37° C. The mixture of cells and compounds was         added into the upper chamber of the 24-well chemotaxis chamber         (Transwell™, Cat.#3421, Costar, pore size; 5 μm). 0.5 ml of 10         nM of human recombinant eotaxin(Cat.#23209, Genzyme Techne)         solution, diluted with chemotaxis buffer, was added into the         lower chamber of the chemotaxis plate. Then, chemotaxis was         performed in CO₂ incubator at 37° C. for 4 hours. After 4 hrs         incubation, migrated cells were counted using FACScan (Becton         Dickinson). The inhibition percent at the each concentration of         compound was calculated, and IC50 values were determined from         the inhibition curve.

[Selectivity Test]

Selectivity test was done in calcium mobilization assay and in receptor binding assay by using CCR1, CCR2, CCR4, CCR5, CCR7, CCR8, CXCR1 and PAR-1 (peptidase activate receptor) stable transformants. Methods for the test are the same as that of CCR3. Only the difference is that different stable transformants were used for these selectivity tests.

[Determination of IC50 Values of Compounds in Chemotaxis Assay with the Use of Human Eosinophils]

Human eosinophils were purified from peripheral blood. Twenty five ml of heparinized blood was layered on 15 ml of Mono-Poly Resolving Medium (#16-980-49DN, ICN Biomedicals Co. Ltd, Japan) in 50 ml tube (#2335-050, Iwaki, Japan) gently and then centrifuged at 400G, for 20 min, at room temperature. After centrifugation, red blood cells were removed by hypotonic lysis. The polymorphonuclear leukocyte pellet was incubated with anti-human CD16 Microbeads (#130-045-701, Milteynyi Biotec GmbH, Germany) for 30 min at 4° C. After washing the cells, magnetically labeled neutrophils were then depleted by applying the cell suspension to BS columns (#130-041-304, Milteynyi Biotec GmbH, Germany) attached to VarioMACS (#130-090-282, Milteynyi Biotec GmbH, Germany).

Chemotaxis assay with the use of the obtained eosinophils was done by the same protocols as that using CCR3 stable transformants, L1.2 cells.

[Primate Chronic Asthma Model: Protocol]

Materials and Methods: The animals used in this study were wild caught, adult male cynomolgus monkeys (Macaca fascicularis) weighing 4.0 to 9.0 kg (Charles River BRF, Inc.). All animals studied demonstrated a naturally occurring respiratory sensitivity to inhaled Ascaris suum extract. Animals were housed individually in environmentally controlled rooms in open mesh cages and provided food twice daily and water ad libitum. Each animal was fasted for approximately 12 hours prior to the day of study. For each study the animals were anesthetized with ketamine hydrochloride (7 mg/kg, i.m.; Ketaset, Fort Dodge, Iowa) and xylazine (1.2 mg/kg, i.m.; Bayer Corp., Elkart, Ind.), incubated with a cuffed endotracheal tube (5.0 mm ID; Mallinckrodt Critical Care, Glen Falls, N.Y.) and seated in a specially designed support chair. Ketamine (5 mg/kg, i.m.) was used to supplement anesthesia as needed.

Study Protocol: Airway responsiveness (AR) to inhaled methachroline followed by bronchoalveolar lavage (BAL) to assess airway cellular composition (ACC) were determined 3 days before (day 0) and 3 days after (day 10) three alternate-day (days 3,5,7) inhalations of Ascaris suum extract. Animals were rested 6 to 8 weeks between studies to allow airway responsiveness and inflammation to return to baseline (pre-antigen) levels. Treatment studies were bracketed by vehicle control studies to assure that no changes in sensitivity to antigen occurred over time.

The test compounds dissolved in Ethanol:PEG400:Water (10:50:40 v/v) were administered under light anesthetisia

Aerosol Delivery System and Inhalation Challenges: Aerosol inhalation challenges were administered by intermittent positive pressure breathing with a Bird Mark 7A respirator and micronebulizer (model 8158). Each challenge consisted of 30 breaths (maximum inspiratory pressure=20 cmH₂O). Ascaris suum extract (Greer Laboratories, Lenoir, N.C.) was diluted with PBS to a final threshold concentration previously determined for each animal and administered as an aerosol (particle size <2 μm). Methacholine (Sigma Chemical Co, St. Louis, Mo.) was dissolved in PBS at a concentration of 100 mg/ml and serial dilutions of 30, 10, 3, 1, 0.3 and 0.1 mg/ml were subsequently prepared for nebulization.

Measurement of Respiratory System Resistance (Rrs): The animal was connected to a Harvard Ventilator (Harvard Apparatus, S. Natick, Mass.) via the endotracheal tube and ventilated at a rate between 30-35 breaths per minute. Airflow was measured by a Fleisch (Hans Rudolph) pneumotachograph and thoracic pressure was measured by a validyne pressure transducer (as the difference between the pressure at the distal end of the endotracheal tube and room pressure). The pneumotachograph and validyne were connected to a pre-amplifier and then into an MI² respiratory analyzer (Malvern, Pa.). Using the primary signals of flow and pressure the analyzer computed airway resistance and compliance (as well as a number of other respiratory parameters).

Methacholine Dose Response Determinations: To assess airway responsiveness to inhaled methacholine, cumulative dose response curves were constructed by administering increasing concentrations of methacholine until increases in Rrs of between 100 and 200% were obtained. A vehicle control challenge was performed prior to the first dose of methacholine. Changes in Rrs were measured continuously over a 10 minute period post aerosol challenge. Aerosol challenges were separated by 5 to 10 minutes or until Rrs returned to baseline values.

Determination of PC₁₀₀ Values: The resistance obtained with PBS was set as zero. The percentage increase in resistance above zero at each dose of methacholine was entered into the computer and the program used an algorithm to determine the exact methacholine concentration which caused an increase in resistance of 100% above baseline (PC₁₀₀). Differences (day 10-day 0) in PC₁₀₀ values were calculated as logs (base 10) to normalize the data and account for the large variation in absolute values for the PC₁₀₀ between animals.

Bronchoalveolar Lavage. Following methacholine dose response determinations each monkey was placed in the supine position and a fiberoptic bronchoscope (Olympus Optical, model 3C-10, Lake Success, N.Y.) was guided past the carina and wedged into a fifth to seventh generation bronchus. A total of 15 ml of bicarbonate buffered saline (pH 7.4) was infused and gently aspirated through a channel in the bronchoscope. Collected samples were immediately centrifuged at 2000 rpm for 10 minutes at 4° C. The resulting pellets were resuspended in Ca++ and Mg++ free Hank's balanced salt solution. To avoid possible effects of the BAL procedure on lung cellular composition, BAL was performed on alternating right and left lungs. Total white cells per milliliter of BAL fluid was obtained using a Coulter counter (Coulter Corp., Miami, Fla.). BAL cell composition was determined by counting a minimum of 200 cells from a Wright's stained cytospin slide preparation.

Blood Samples: Blood samples were collected prior to and 30 minutes, 1 hr and 2 hr after the first dose of the test compounds (morning of day 2), immediately before each subsequent dose, and 30 minutes, 1 hr and 2 hr after the final dose (evening of day 9). Blood was collected from the femoral vein into EDTA, centrifuged at 1500 rpm for 15 minutes at 4° C. and the plasma stored at −70° C. until assayed for the test compounds.

Statistical Analysis: All data were evaluated statistically with the use of students t-test where a p value <0.05 was considered statistically significant.

Results of receptor binding assay (RBA), Ca²⁺ mobilization assay (Ca²⁺) are shown in Examples and tables of the Examples below. The data corresponds to the compounds as yielded by solid phase synthesis and thus to levels of purity of about 40 to 90%. For practical reasons, the compounds are grouped in three classes of activity as follows: IC₅₀=A1 μM<B10 μM<C

The compounds of the present invention also show more than 100-fold selectivity against CCR1, CCR5, CCR7. CCR8 and CXCR1 in receptor binding assays.

The compounds of the present invention show dose-dependent inhibitory effect on eotaxin-induced chemotaxis of human eosinophils and strong activity in vivo assays.

Example 1-1

-   (1) To the solution of 2-chloro-5-nitrobenzenesulfonyl chloride     (3.84 g, 15 mmol) in dry THF (30 ml) was added dropwise the mixture     of Boc-piperazine (3.07 g, 16.5 mmol) and N,N-diisopropylethylamine     (2.33 g, 18 mmol) in dry THF (10 ml) at 0° C. with stirring. The     mixture was then stirred at room temperature for 3 hrs. The solvent     was evaporated and CH₂Cl₂ was added to the residue. The mixture was     washed with 0.5 N aqueous HCl, brine, saturated aqueous NaHCO₃,     brine, successively, dried over MgSO₄. The solvent was evaporated to     give tert-butyl     4-[(2-chloro-5-nitrophenyl)sulfonyl]-1-piperazinecarboxylate as     white powder (5.80 g, 95.3%).

-   (2) To the solution of 3,5-dimethylphenol (1.92 g, 15.72 mmol) in     DMF (50 ml) was added NaH (60%, 0.629 g, 15.72 mmol) at 0° C. with     stirring. tert-Butyl     4-[(2-chloro-5-nitrophenyl)sulfonyl]-1-piperazinecarboxylate (5.80     g, 14.29 mmol) was added to the mixture after 30 min. The mixture     was stirred at room temperature for 2 hrs. 100 ml of ice water was     added, the precipitate was collected by filtration, washed with     water and dried in vacuo to give tert-butyl     4-([2-(3,5-dimethylphenoxy)-5-nitrophenyl]sulfonyl}-1-piperazinecarboxylate     as white powder (6.90 g, 98.2%): mp 232-233° C.; ¹H NMR (500 MHz,     CDCl3). 1.45 (9H, s), 2.35 (6H, s), 3.35 (4H, t, J=5 Hz), 3.51 (4H,     t, J=5 Hz), 6.72 (2H, s), 6.91-6.95 (2H, m), 8.26 (1H, t), 8.86 (1H,     s); HPLC-MS (ESI): Calcd for C₂₃H₂₉N₃O₇S [M+H]⁺ 492, Found: 492. -   Molecular weight: 491.5675 -   Activity grade RBA: C -   Activity grade Ca²⁺: C

Example 1-2

-   (1) To the suspension of tert-butyl     4-{[2-(3,5-dimethylphenoxy)-5-nitrophenyl]-sulfonyl}-1-piperazinecarboxylate     (620 mg, 1.26 mmol) which was prepared in the Example 1-1 in CH₂Cl₂     (3 ml) was added trifluoloacetic acid (2 ml) at 0° C., the mixture     was stirred at 0° C. for 3 hrs. The solvent was evaporated in vacuo     and 20 ml of toluene was added, the solvent was evaporated in vacuo     again. To the residue was added CH₂Cl₂ (15 ml), and the mixture was     cooled to 0° C. 4 N HCl solution in 1,4-dioxane (2 ml) was added and     the mixture was stirred for 15 mini at 0° C. The solvent was     evaporated, and diethyl ether (5 ml) was added to the residue. The     precipitate was collected by filtration and dried to give     1-{[2-(3,5-dimethylphenoxy)-5-nitrophenyl]sulfonyl}piperazine     hydrochloride

(480 mg, 88.9%): mp 264-266° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 2.33 (6H, s), 3.18 (4H, br), 3.56 (4H, br), 6.96 (2H, s), 7.03-7.05 (2H, m), 8.45 (1H, q, J=9.2 Hz), 8.60 (H, d, J=2.8 Hz), 9.38 (2H, br); HPLC-MS (ESI): Calcd for C₁₈H₂₁N₃O₅S [M+H]⁺ 392, Found: 392.

-   Molecular weight: 427.9101 -   Activity grade RBA: A -   Activity grade Ca²⁺: A

In the similar manner as described in Example 1-1 or 1-2 above, compounds in Example 1-3 to 1-100 as shown in Table 1 were synthesized.

TABLE 1 EX. No. molstructure MW M + 1 mp RBA Ca2+ 1-3

505.47344 392 120-125 A A 1-4

435.83682 400 273-274 A A 1-5

459.90894 424 211-213 C C 1-6

535.85272 500 188-191 A A 1-7

512.07268 476 141-143 C C 1-8

455.96432 420 182-185 A A 1-9

441.93723 406 168-170 A A 1-10

424.86584 389 265-267 B B 1-11

449.9165 414 196-198 B A 1-12

413.88305 378 167-169 B B 1-13

487.79257 379 246-248 C C 1-14

381.38542 382 118-120 B 1-15

417.84639 382 227-229 B 1-16

413.88305 378 188-192 C 1-17

413.88305 378 242-244 A 1-18

477.41926 363 B B 1-19

407.44575 394 C C 1-20

495.40969 382 C C 1-21

533.52762 420 C C 1-22

511.86429 398 C C 1-23

502.42914 1-24

491.44635 378 A A 1-25

495.40969 382 A A 1-26

567.55814 495 214-220 1-27

429.88245 394 142 A A 1-28

434.30099 398 166-169 B A 1-29

424.86584 389 133 B B 1-30

441.8936 406 194-200 C C 1-31

441.8936 406 77 C C 1-32

442.92481 407 182 C B 1-33

468.74602 432 260-264 A A 1-34

467.85434 432 128 A A 1-35

461.0025 425 267-268 B A 1-36

455.96432 420 155 B A 1-37

443.90954 408 113 A A 1-38

444.85349 409 150 B A 1-39

478.75199 442 119 A A 1-40

455.96432 420 140-150 A A 1-41

382.91261 347 205-207 C B 1-42

531.50589 459 288-290 C C 1-43

450.91099 415 238-239 A A 1-44

441.93723 406 159 B B 1-45

482.77311 446 168 A A 1-46

450.91099 415 250-251 C C 1-47

457.93663 422 188 B C 1-48

408.81135 471 170 A A 1-49

412.9391 377 125 A 1-50

498.77251 462 181 A 1-51

441.73892 405 145 A A 1-52

396.9397 361 136 A 1-53

495.34155 423 amorphous B 1-54

455.96432 420 159 A A 1-55

471.74954 n.d. 231 A 1-56

458.19352 421 255-257 A A 1-57

502.64452 467 269-271 A A 1-58

400.90304 365 204 A 1-59

441.73892 405 306 A 1-60

448.32808 412 204 B B 1-61

441.93723 406 220 B B 1-62

427.91014 392 142 A A 1-63

427.91014 392 142 B A 1-64

427.91014 392 141 A A 1-65

441.93723 406 187 A A 1-66

455.96432 420 193 B B 1-67

414.87063 379 248 A 1-68

475.95474 440  99 A 1-69

441.93723 406 248 A 1-70

414.87063 379 237 A 1-71

429.88245 394 182 A 1-72

453.94838 418 168 A 1-73

489.80811 454 297 A 1-74

471.81768 436 104 A A 1-75

458.88058 423 215 A 1-76

557.64802 521 205 A A 1-77

486.73645 450 263 A A 1-78

482.77311 445 >300 A 1-79

462.35517 427 178-179 A A 1-80

448.32808 413 166-167 A A 1-81

490.40935 455 C C 1-82

468.74602 433 173-174 B 1-83

468.74602 433 167-168 C 1-84

468.74602 433 179-180 A A 1-85

452.29142 417 172-173 1-86

503.19105 468 188-189 A A 1-87

512.75597 475 240-241 A A 1-88

435.50275 436 163-164 A A 1-89

479.55633 480 A A 1-90

441.93723 406 A A 1-91

482.77311 446 261-263 A A 1-92

455.96432 420 A A 1-93

496.8002 460 A A 1-94

455.96432 420 >300 A 1-95

442.70778 446 220-221 A 1-96

496.8002 A 1-97

460.33923 460 148-151 A 1-98

504.34918 504 200-201 A 1-99

468.74602 432 247-250 A 1-100

468.74602 432 256-258 A A

Example 2-1

-   (1) To the solution of 3,5-dimethylthiophenol (82.94 mg, 0.60 mmol)     in dry THF (5 ml) was added NaH (60%, 24 mg, 0.60 mmol). tert-Butyl     4-[(2-chloro-5-nitrophenyl)sulfonyl]-1-piperazinecarboxylate (162     mg, 0.4 mmol), which was prepared in the step (1) of Example 1-1,     was added to the solution after 10 min. The resulting mixture was     stirred at room temperature overnight. 60 mg of K₂CO₃ was added and     the mixture was stirred at room temperature for 6 hrs. EtoAc was     added and the mixture was washed by 10% aqueous Na₂CO₃, brine,     successively. The organic layer was dried over MgSO₄. The solvent     was evaporated to 3 ml, the produced white crystal was collected by     filtration and dried to give tert-butyl     4-({2-[(3,5-dimethylphenyl)sulfanyl]-5-nitrophenyl}-sulfonyl)-1-piperazinecarboxylate     (148 mg, 72.9%).

-   (2) To the solution of tert-butyl     4-({2-[(3,5-dimethylphenyl)sulfanyl]-5-nitrophenyl}sulfonyl)-1-piperazinecarboxylate     (100 mg, 0.20 mmol) in dry CH₂Cl₂ (3 ml) was added 4 N HCl (0.5 ml)     solution in 1,4-dioxane, the mixture was stirred overnight at room     temperature. The solvent was evaporated, and 5 ml of diethyl ether     was added to the residue. The precipitate was collected by     filtration and dried to give     1-({2-[(3,5-dimethylphenyl)sulfanyl]-5-nitrophenyl}sulfonyl)piperazine     hydrochloride (82 mg, 93.8%): mp 225-227° C.; ¹H NMR (300 MHz,     DMSO-d₆) δ 2.34 (6H, s), 3.18 (4H, br), 3.63 (4H, br), 7.09 (1H, d,     J=9 Hz), 7.25 (1H, s), 7.31 (2H, s), 8.30 (1H, q, J=9 Hz), 8.54 (1H,     d, J=2), 9.57 (2H, br); HPLC-MS (ES): Calcd for C₁₈H₂₁N₃O₄S₂ [M+H]⁺     408, Found: 408. -   Molecular weight: 443.9747 -   Activity grade RBA: A -   Activity grade Ca²⁺: A

In the similar manner as described in Example 2-1 above, compounds in Example 2-2 to 2-24 as shown in Table 2 were synthesized.

TABLE 2 EX. No. molstructure MW M + 1 mp RBA Ca2+ 2-2

532.46856 533 147-148 A 2-3

530.49625 531 191-192 A A 2-4

492.44686 492 A 2-5

458.77238 421 189 A 2-6

548.46796 548 156-158 A 2-7

476.40383 476 147-149 A 2-8

512.8648 476 205-207 A 2-9

520.45741 520 131-133 A 2-10

520.41378 520 209-211 A 2-11

484.81062 448 270 A A 2-12

484.81062 449 263 A A 2-13

518.4851 518 A A 2-14

415.92056 380 B 2-15

458.00183 422 274 B 2-16

429.94765 394 229-231 A 2-17

450.36559 414 235-237 A 2-18

484.81062 448 262-264 A 2-19

433.91099 398 236-238 A 2-20

551.91732 516 230-231 A 2-21

465.9811 430 273 B 2-22

516.46916 516 213 A A 2-23

464.39268 464 102 A A 2-24

490.43092 490 A A

Example 3-1

-   (1) To the solution of 3,5-dimethylaniline (96.9 mg, 0.80 mmol) in     dry THF (15 ml) was added NaH (60%, 24 mg, 0.6 mmol) followed by     tert-butyl     4[(2-chloro-5-nitrophenyl)sulfonyl]-1-piperazinecarboxylate (162.3     mg, 0.40 mmol), which was prepared in the step (1) of Example 1-1     and the mixture was stirred at 80° C. for 2 hrs. The solvent was     evaporated and 15 ml of ice water was added to the residue. The     mixture was extracted with CH₂Cl₂. The combined extract was washed     with saturated aqueous NaHCO₃, brine, successively, dried over     MgSO₄. The solvent was evaporated and 10 ml of diethyl ether was     added to the residue, the produced precipitate was collected by     filtration and dried to give tert-butyl     4-({2-[(3,5-dimethylphenyl)amino]-5-nitrophenyl}-sulfonyl)-1-piperazinecarboxylate     (110 mg, 56.1%).

-   (2) To the suspension of tert-butyl     4-({2-[(3,5-dimethylphenyl)amino]-5-nitrophenyl}sulfonyl)-1-piperazinecarboxylate     (150 mg, 0.31 mmol) in CH₂Cl₂ (2 ml) was added 4N HCl solution in     1,4-dioxane (1 ml), the mixture was stirred for 2 hrs at room     temperature. The mixture was filtered. The filtrate was evaporated,     and 5 ml of diethyl ether was added to the residue. The precipitate     was collected by filtration and dried to give     N-(3,5-dimethylphenyl)₄-nitro-2-(1-piperazinylsulfonyl)aniline     dihydrochloride (115 mg, 81.2%): mp 175-179° C.; ¹H NMR (300 MHz,     DMSO-d₆) δ 2.30 (6H, s), 3.18 (4H, t, J=5.3 Hz), 3.44 (4H, q, J=5.3     Hz), 6.97 (3H, s), 7.10 (1H, d, J=9.4 Hz), 8.25 (1H, q, J=9.4 Hz),     8.34 (1H, d, J=2.64 Hz), 8.47 (1H, s), 9.23 (2H, br); HPLC-MS (ESI):     Calcd for C₁₈H₂₂N₄O₄S [M+H]⁺ 391, Found: 391. -   Molecular weight: 463.3864 -   Activity grade RBA: A

In the similar manner as described in Example 3-1 above, compounds in Example 3-2 to 3-12 as shown in Table 3 were synthesized.

TABLE 3 EX.No. molstructure MW M + 1 mp RBA Ca2+ 3-2

467.76129 431 160 A A 3-3

412.89832 377 155 B B 3-4

412.89832 377 158 B B 3-5

412.89832 377 239-240 C B 3-6

433.31626 397 C B 3-7

433.31626 397 150 A 3-8

433.31626 397 267 A 3-9

416.86166 381 275 A  3-10

416.86166 381 A  3-11

416.86166 381 A  3-12

428.89772 393 241-242 A

Example 4-1

-   (1) To the solution of 2-chloro-5-nitrobenzenesulfonyl chloride     (2.05 g, 8 mmol) in THF (60 ml) was added the solution of     4-(1-pyrrolidinyl)piperidine (1.23 g, 8 mmol) and NEt₃ (0.89 g, 8.8     mmol) in THF (15 ml) dropwise. The mixture was stirred at room     temperature for 2 hrs. 3,5-Dichlorophenol (1.96 g, 12 mmol) was     added to the above mixture followed by NaH (60%, 0.96 g, 12 mmol).     The resulting mixture was stirred at 65° C. for 8 hrs, and cooled to     room temperature. The precipitate was collected by filtration and     washed with THF, Et₂O, and water, successively, dried in vacuo to     give     1-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-4-(1-pyrrolidinyl)piperidine     as white powder (3.2 g, 79.9%): mp 217-218° C.; ¹H NMR (500 MHz,     CDCl3) δ 1.26 (2H, s), 1.63 (4H, d, J=10 Hz), 1.77 (4H, s), 1.92     (2H, d, J=6.1 Hz), 2.15 (1H, m), 2.34 (6H, s), 2.97 (2H, p, J=10     Hz), 3.86 (2H, q, J=9.3 Hz), 6.74 (2H, s), 6.90 (1H, d, J=9.1 Hz),     6.94 (1H, s), 8.24 (1H, q, J=9.1 Hz), 8.86 (1H, d, J=2.85 Hz):     HPLC-MS (ESI): Calcd for C₂₁H₂₃Cl₂N₃O₅S [M+H]⁺ 501, Found: 500 and     502 -   Molecular weight: 500.4046 -   IC₅₀ (CCR3): 8 μM -   IC₅₀ (Ca²⁺): 7 μM -   IC₅₀ (Chemotaxis): 5 μM

In the similar manner as described in Example 4-1 above, compounds in Example 4-2 to 4-41 as shown in Table 4 were synthesized.

TABLE 4 EX.No. molstructure MW M + 1 mp RBA Ca2+ 4-2 

433.53044 434 A A 4-3 

435.50275 436 B A 4-4 

405.47626 406 131-132 A A 4-5 

419.50335 420 111-112 A A 4-6 

473.59577 474 190-192 A A 4-7 

467.54795 468 168-169 C C 4-8 

481.57504 482 168-170 C C 4-9 

481.57504 482 123-124 C 4-10

419.45972 437 210-212 C 4-11

459.56868 460 156-158 A 4-12

447.55753 448 86-88 A A 4-13

419.50335 420 115-116 A A 4-14

407.4922 408 75-77 A A 4-15

433.53044 434 129-131 A A 4-16

447.55753 448 134-135 A A 4-17

461.58462 462 93-95 A A 4-18

461.58462 462 131-132 A B 4-19

459.56868 460 169-171 A A 4-20

448.32808 448 105-107 A A 4-21

488.39341 488 120-121 A A 4-22

500.40456 500 200-202 A A 4-23

460.33923 460 A A 4-24

469.99141 434 262-264 A A 4-25

482.34559 483 226 B 4-26

475.56808 476 178-179 A A 4-27

516.40396 517 182-183 A A 4-28

491.63268 492 143-144 A 4-29

514.43165 515 173-174 A A 4-30

531.46226 531 98-99 A 4-31

503.40808 503 138-140 A 4-32

529.44632 529 167-169 A 4-33

487.50173 488 A A 4-34

528.33761 528 166-167 A A 4-35

476.38226 476 134 A 4-36

504.39281 504 145 A A 4-37

532.40336 532 160-162 A 4-38

486.37747 486 A A 4-39

462.35517 462 A 4-40

502.4205 502 A 4-41

474.36632 474 A

Example 5-1

-   (1) The mixture of tert-butyl     4-{[2-(3,5-dimethylphenoxy)-5-nitrophenyl]-sulfonyl}-1-piperazinecarboxylate     (6.80 g, 13.83 mmol), which was prepared in the step (2) of Example     1-1 and 10% Pd-C (1) in methanol (600 ml) was stirred at room     temperature under 1 ATM of H₂ for 5 hrs. The Pa—C was filtered off.     The filtrate was evaporated to 30 ml. The produced crystals was     collected by filtration to give tert-butyl     4-{[5-amino-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-1-piperazinecarboxylate     (6.0 g, 94.0%).: HPLC-MS (ESI): Calcd for C₂₃H₃₁N₃O₅S [M+H]⁺ 462,     Found: 462. -   Molecular weight: 461.5846 -   Activity grade RBA: C -   Activity grade Ca²⁺: C

Example 5-2

-   (1) To the mixture of copper(I) chloride (39.6 mg, 0.4 mmol) and     tert-butyl nitrite (41.2 mg, 0.4 mmol) in CH₃CN (10 ml) was added     tert-butyl     4-{[5-amino-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-1-piperazinecarboxylate     (92.3 mg, 0.2 mmol) which was prepared in the Example 5-1 at 60° C.     The mixture was stirred at 65-70° C. for 2 hrs, and cooled to room     temperature. The solvent was evaporated. CH₂Cl₂ was added to the     residue and the mixture was washed with 15 ml of 4N NaOH, 30 ml of     brine, successively, dried over MgSO₄. The solvent was evaporated,     and the residue was purified by preparative TLC on silica gel     (CH₂Cl₂/CH₃OH=35/1) to give     tert-butyl-4-{[5-chloro-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-1-piperazinecarboxylate     (56.0 mg, 58.2%).

-   (2) To the suspension of tert-butyl     4-{[5-chloro-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-1-piperazinecarboxylate     (40.0 mg, 0.08 mmol) in dry CH₂Cl₂ (1.5 ml) was added 0.3 ml of 4N     hydrogen chloride solution in 1,4-dioxane, the mixture was stirred     for 5 hrs at room temperature. The solvent was evaporated, and     diethyl ether (5 ml) was added to the residue. The produced     precipitate was collected by filtration and dried to give     1-{[5-chloro-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}piperazine     hydrochloride (24.0 mg, 69.2%): mp 202-204° C.; 1H NMR (300 MHz,     DMSO-d6) δ 2.30 (6H, s), 3.14 (4H, be), 3.50 (4H, br), 6.82 (2H, s),     6.91 (1H, s), 6.97 (1H, d, J=8.7 Hz), 7.70 (1H, t, J=8.7 Hz), 7.82     (1H, d, J=2.3 Hz), 9.57 (2H, br); HPLC-MS (ESI): Calcd for     C₁₈H₂₁ClN₂O₃S [M+H]⁺ 381, Found: 381. -   Molecular weight: 417.3576 -   Activity grade RBA: A -   Activity grade Ca²⁺: A

In the similar manner as described in Example 5-1 or 5-2 above, compounds in Example 5-3 to 5-8 as shown in Table 5 were synthesized.

TABLE 5 EX.No. molstructure MW M + 1 mp RBA Ca2+ 5-3

475.49058 362 133-135 C C 5-4

408.95085 409 120-122 A A 5-5

500.40225 501 133-134 A A 5-6

508.80904 473 241-243 A A 5-7

448.41534 376 183 C C 5-8

431.38473 395 148 A

Example 6-1

-   (1) To the solution of tert-butyl     4-{[5-amino-2-(3,5-dimethylphenoxy)phenyl]-sulfonyl}-1-piperazinecarboxylate     (138.5 mg, 0.30 mmol) prepared in the step (1) of Example 5-1 in     CH₂Cl₂ (5 ml) was added nitrosonium tetrafluoroborate (38.5 mg, 0.33     mmol) at 0° C. and the solution was stirred at 0° C. for 30 min. The     solvent was evaporated. The residue was dissolved in methanol (5 ml)     and the solution of Cu₂O (64.4 mg, 0.45 mmol) and CuSO₄.3H₂O (724.8     mg, 3 mmol) in 10 ml of water was added to the above solution at     0° C. The mixture was stirred at 0° C. for 30 min. The solvent was     evaporated and ethyl acetate was added. The mixture was washed with     1 N aqueous NaOH, brine, successively and dried over MgSO₄. The     solvent was evaporated and the residue was purified by preparative     TLC on silica gel (CH₂Cl₂/CH₃OH=20/1) to give tert-butyl     4-{[2-(3,5-dimethylphenoxy)-5-hydroxyphenyl]-sulfonyl}-1-piperazinecarboxylate     (39.0 mg, 28.1%).

-   (2) To the suspension of tert-butyl     4-{[2-(3,5-dimethylphenoxy)-5-hydroxyphenyl]sulfonyl}-1-piperazinecarboxylate     (12.0 mg, 0.03 mmol) in dry CH₂Cl₂ (1 ml) was added 4 N HCl solution     in 1,4-dioxane (0.18 ml), the mixture was stirred 5 hrs at room     temperature. The solvent was evaporated, and 3 ml of diethyl ether     was added to the residue. The precipitate was collected by     filtration and dried to give     4-(3,5-dimethylphenoxy)-3-(1-piperazinylsulfonyl)phenol     hydrochloride (9.0 mg, 87.0%): mp >286; 1H NMR (300 MHz, DMSO-d6) δ     2.24 (6H, s), 3.12 (4H, br), 3.36 (4H, br), 6.56 (2H, s), 6.76 (1H,     s), 6.96 (1H, d, J=9 Hz), 7.08 (1H, q, J=9 Hz), 7.25 (1H, d, J=2.6     Hz), 9.03 (2H, br), 10.06 (1H, s); HPLC-MS (ESI): Calcd for     C₁₈H₂₂N₂O₄S [M+H]⁺ 363, Found: 363. -   Molecular weight: 398.9120 -   Activity grade RBA: C -   Activity grade Ca²⁺: C

Example 6-2

-   (1) To the solution of tert-butyl     4-{[2-(3,5-dimethylphenoxy)-5-hydroxyphenyl]-sulfonyl}-1-piperazinecarboxylate     (20.0 mg, 0.04 mmol), which was prepared in the step (1) of Example     6-1 in dry DMF (1 ml) was added methyl iodide (30.7 mg, 0.22 mmol)     and K₂CO₃ (12.0 mg, 0.09 mmol). The mixture was stirred at room     temperature for 3 hrs. The solvent was evaporated in vacuo and 3 ml     of ice water was added. The white precipitate was collected by     filtration and washed with 1 N aqueous NaOH, water and dried to give     tert-butyl     4-{[2-(3,5-dimethylphenoxy)-5-methoxyphenyl]sulfonyl}-1-piperazinecarboxylate     as white powder (20.0 mg, 97.1%).

-   (2) To the solution of tert-butyl     4-{[2-(3,5-dimethylphenoxy)-5-methoxyphenyl]-sulfonyl}-1-piperazinecarboxylate     (18.0 mg, 0.04 mmol) in dry CH₂Cl₂ (1 ml) was added 4 N HCl (0.2 ml)     solution in 1,4-dioxane, the mixture was stirred hrs at room     temperature. The solvent was evaporated, and 3 ml of diethyl ether     was added to the residue. The precipitate was collected by     filtration and dried to give     4-(3,5-dimethylphenoxy)-3-(1-piperazinylsulfonyl)phenol     hydrochloride (12.0 mg, 76.9%): mp 175-177° C.; 1H NMR (300 MHz,     DMSO-d6) δ 2.25 (6H, s), 3.12 (4H, t, J=4.5 Hz), 3.40 (4H, d, J=4.5     Hz), 3.82 (3H, s), 6.62 (2H, s), 6.80 (1H, s), 7.04 (1H, d, J=9.1     Hz), 7.27 (1H, q, J=9.1 Hz), 7.33 (1H, d, J=3.0 Hz), 9.24 (2H, br);     HPLC-MS (ES): Calcd for C₁₉H₂₄N₂O₄S [M+H]⁺ 377, Found: 377. -   Molecular weight: 412.9391 -   Activity grade RBA: A -   Activity grade Ca²⁺: B

In the similar manner as described in Example 6-1 or 6-2 above, compounds in Example 6-3, 6-4 and 6-5 as shown in Table 6 were synthesized.

TABLE 6 EX.No. molstructure MW M + 1 mp RBA Ca2+ 6-3

364.4421 365 116-118 A A 6-4

412.2974 412 179-181  9  7 6-5

480.4169 480 186-187 20 17

Example 7-1

-   (1) To the mixture of tert-butyl     4-{[5-amino-2-(3,5-dimethylphenoxy)phenyl]-sulfonyl}-1-piperazinecarboxylate     (369 mg, 0.80 mmol), which was prepared in the step (1) of Example     5-1, and triethylamine (97 mg, 0.96 mmol) in dry CH₂Cl₂ (20 ml) was     added dropwise the solution of phenylacetyl chloride (130 mg, 0.84     mmol) in THF (5 ml) at 0° C. with stirring. The mixture was then     stirred at RT for 3 hrs, and CH₂Cl₂ was added. The mixture was     washed with 0.5 N aqueous HCl, brine, saturated aqueous NaHCO₃,     brine, successively, dried over MgSO₄. The solvent was evaporated.     Dry CH₂Cl₂ (15 ml) was added to the residue. 4 N HCl solution in     2,4-dioxane (1 ml) was added to the solution at 0° C. with stirring.     The mixture was then stirred at room temperature for 3 hrs. The     obtained precipitate was collected to give product as HCl salt. The     HCl salt was suspended in 10 ml of ice water and the PH of the     mixture was adjusted to 8 by addition of saturated aqueous NaHCO₃,     extracted by CH₂Cl₂. The combined extract was washed with saturated     aqueous NaHCO₃, brine, successively, dried over MgSO₄. The solvent     was evaporated. 5 ml of methanol was added to the residue and the     white precipitate was collected by filtration and washed with ether     and dried to give     N-[4-(3,5-dimethylphenoxy)-3-(1-piperazinylsulfonyl)phenyl]-2-phenylacetamide     (330 mg, 86.0%): mp 228-230° C.; 1H NMR (300 MHz, CDCl3). 2.28 (6H,     s), 2.87 (4H, br), 3.24 (4H, br), 3.74 (2H, s), 6.62 (2H, s), 6.79     (1H, s), 6.87 (1H, d, J=8.8 Hz), 7.34-7.62 (6H, m), 7.62 (1H, s),     7.95 (1H, q, J=8.8 Hz); HPLC-MS (ESI): Calcd for C₂₆H₂₉N₃O₄S [M+H]⁺     480, Found: 480. -   Molecular weight: 479.6027 -   Activity grade RBA: C -   Activity grade Ca²⁺: C

In the similar manner as described in Example 7-1 above, compounds in Example 7-2 to 7-9 as shown in Table 7 were synthesized.

TABLE 7 EX.No. molstructure MW M + 1 mp RBA Ca2+ 7-2

403.504 404 C C 7-3

445.5852 446 C C 7-4

445.5852 446 C C 7-5

502.0366 466 C C 7-6

516.0637 484 C C 7-7

552.0972 516 C B 7-8

493.6298 494 C C 7-9

471.6014 472 C C

Example 8-1

-   (1) To a solution of 4-bromoanisole (2.00 g, 10.7 mmol) in CHCl₃     (20 ml) was added chlorosulfonic acid (1.49 ml, 22.5 mmol) at 0° C.     This mixture was stirred at room temperature for 2 hrs, and then     poured into ice water (50 ml). This mixture was extracted with     CH₂Cl₂. The combined organic extracts were washed with brine, dried     over anhydrous MgSO₄, filtered, and concentrated to give crude     5-bromo-2-methoxybenzenesulfonyl chloride (0.760 g, 24.9%).

-   (2) To a solution of 5-bromo-2-methoxybenzenesulfonyl chloride (760     mg, 2.66 mmol) and Et₃N (445 μl, 3.19 mmol) in CH₂Cl₂ (20 ml) was     added 1-(t-butoxycarbonyl)piperazine (521 mg, 2.80 mmol) at 0° C.     This mixture was stirred at room temperature for 6 hrs, and then     diluted with Et₂O, washed with 10% citric acid solution, aqueous     NaHCO₃, and brine. The organic layer was dried over anhydrous     Na₂SO₄, filtered, and concentrated to give crude sulfonamide (716     mg).

To a solution of the sulfonamide (716 mg, 1.65 mmol) in CH₂Cl₂ (5 ml) was added 1M BBr₃ solution in CH₂Cl₂ (3.30 ml, 3.30 mmol) at 0° C. This mixture was stirred at 0° C. for 1 hr. After basifing with 3M aqueous NaOH (20 ml), THF (15 ml) and Di-t-butyl dicabonate (718 mg, 3.29 mmol) were added to the mixture at 0° C. The mixture was stirred at room temperature overnight. This mixture was extracted with Et₂O. The organic extract was dried over anhydrous Na₂SO₄, filtered, and concentrated to give di(Boc)-compound. To hydrolize t-butyl carbonate, the residue was treated with K₂CO₃ (455 mg, 3.29 mmol) in MeOH (10 ml) at room temperature for 5 hrs. After removing MeOH by evaporation, the residue was acidified with 10% citric acid solution. This aqueous mixture was extracted with EtoAc. The organic extract was dried over anhydrous Na₂SO₄, filtered, and concentrated to give tert-butyl 4-[(5-bromo-2-hydroxyphenyl)sulfonyl]-1-piperazinecarboxylate (526 mg, 47.0%).

-   (3) To a mixture of tert-butyl     4-[(5-bromo-2-hydroxyphenyl)sulfonyl]-1-piperazinecarboxylate (410     mg, 0.973 mmol), 3,5-dimethylphenylbronic acid (219 mg, 1.46 mmol),     Cu(OAc)₂ (177 mg, 0.973 mmol), and powdered 4A molecular sieves (820     mg) in CH₂Cl₂ (10 ml) was added Et₃N (0.678 ml, 4.87 mmol) at room     temperature. This mixture was stirred at room temperature under     ambient atmosphere overnight. The resulting slurry was filtered     through Celite. The filtrate was diluted with EtoAc, and washed with     aqueous NH₄Cl, NaHCO₃, and brine. The organic layer was dried over     anhydrous Na₂SO₄, filtered, and concentrated. Et₂O was added to the     residue. The resulting precipitate was collected by filtration, and     washed with Et₂O. This solid was purified by column chromatography     on silica gel (CHCl₃/MeOH=99/1) to give tert-butyl     4-{[5-bromo-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-1-piperazinecarboxylate     (320 mg, 62.6%).

-   (4) To a solution of tert-butyl     4-{[5-bromo-2-(3,5-dimethylphenoxy)phenyl]-sulfonyl}-1-piperazinecarboxylate     (25.0 mg, 48.0 μmol) in CH₂Cl₂ (1.0 ml) was added 4M HCl solution in     1,4-dioxane (100 μl, 400 μmol) at 0° C. This mixture was stirred at     room temperature overnight. Solvents were removed by evaporation.     The resulting residue was suspended in Et₂O, and collected by     filtration to give a white amorphous,     1-{[5-bromo-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}piperazine     hydrochloride (20.0 mg, 90.2%): ¹H NMR (300 MHz, CDCl₃) δ 2.31 (6H,     s), 3.12-3.38 (4H, br), 3.60-3.84 (4H, br), 6.72 (2H, s), 6.75 (1H,     d, J=8.7 Hz), 6.87 (1H, s), 7.54 (1H, dd, J=2.3, 8.7 Hz), 8.05 (1H,     d, J=2.3 Hz), 9.79-10.40 (2H, br); HPLC-MS (ESI): Calcd for     C₁₈H₂₁BrN₂O₃S [M+H]⁺ 425 and 427, Found: 425 and 427. -   Molecular weight: 461.8086 -   Activity grade RBA: A -   Activity grade Ca²⁺: A

Example 9-1

-   (1) A mixture of tert-butyl     4-{[5-bromo-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-1-piperazinecarboxylate     (95.0 mg, 181 μmol), which was prepared in the step (3) of Example     8-1, CuCN (32.4 mg, 362 μmol), and Pd(PPh₃)₄ (20.9 mg, 18.1 μmol) in     DMF (2 ml) was heated at 150° C. overnight. After cooling to room     temperature, this mixture was diluted with CH₂Cl₂, and washed with     ammonia solution and brine. The organic layer was dried over     anhydrous Na₂SO₄, filtered, and concentrated. The residue was     purified by column chromatography on silica gel     (Hexane/EtoAc=3/1˜2/1) to give tert-butyl     4-{[5-cyano-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-1-piperazinecarboxylate     (14.0 mg, 16.4%).

-   (2) To a solution of tert-butyl     4-{[5-cyano-2-(3,5-dimethylphenoxy)phenyl]-sulfonyl}-1-piperazinecarboxylate     (14.0 mg, 29.7 μmol) in CH₂Cl₂ (1.0 ml) was added 4M HCl solution in     dioxane (0.2 ml) at room temperature. This mixture was stirred at     room temperature overnight. Dioxane was removed by evaporation. The     residue was suspended in Et₂O. The resulting precipitate was     collected by filtration to give     4-(3,5-dimethylphenoxy)-3-(1-piperazinylsulfonyl)benzonitrile     hydrochloride (6.0 mg, 49.6%): ¹H NMR (300 MHz, CDCl₃) δ 2.34 (6H,     s), 3.28-3.47 (4H, br), 3.67-3.83 (4H, br), 6.78 (2H, s), 6.89 (1H,     d, J=8.6 Hz), 6.95 (1H, s), 7.69 (1H, dd, J=1.9, 8.6 Hz), 8.24 (1H,     d, J=1.9 Hz), 9.97-10.32 (2H, br); HPLC-MS (ESI): Calcd for     C₁₉H₂₁N₃O₃S [M+H]⁺ 372, Found: 372. -   Molecular weight: 407.9225 -   Activity grade RBA: A -   Activity grade Ca²⁺: A

Example 10-1

-   (1) To 4-chlorobenzoic acid (1.00 g, 6.39 mmol) was added     chlorosulfonic acid (2.55 ml, 38.3 mmol) at room temperature     dropwise. This mixture was heated at 150° C. for 6 hrs. After     cooling to room temperature, the mixture was diluted with CH₂Cl₂.     This solution was added to ice water. Two phases were separated. The     organic phase was washed with brine, and then dried over anhydrous     MgSO₄, filtered, and concentrated to give crude     4-chloro-3-(chlorosulfonyl)benzoic acid (0.720 g, 43.9%).

(2) To a solution of 4-chloro-3-(chlorosulfonyl)benzoic acid (200 mg, 0.784 mmol) and Et₃N (130 μl, 0.938 mmol) in CH₂Cl₂ (5 ml) was added 1-(t-butoxycarbonyl)piperazine (161 mg, 0.864 mmol) at 0° C. This mixture was stirred at room temperature overnight, and then diluted with CH₂Cl₂, washed with 10% citric acid solution. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was suspended in Et₂O, and the precipitate was collected by filtration to give crude 3-{[4-(tert-butoxycarbonyl)-1-piperazinyl]sulfonyl}-4-chlorobenzoic acid (200 mg, 63.0%).

-   (3) To a mixture of     3-{[4-(tert-butoxycarbonyl)-1-piperazinyl]sulfonyl}-4-chlorobenzoic     acid (340 mg, 0.840 mmol), dimethylammonium chloride (137 mg, 1.68     mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride     (193 mg, 1.01 mmol), and HOBT (136 mg, 1.01 mmol) in CH₂Cl₂ was     added Et₃N (410 μl, 2.96 mmol) at 0° C. This mixture was stirred at     room temperature for two days. The mixture was diluted with EtoAc,     and washed with 10% citric acid solution, aqueous NaHCO₃, and brine.     The organic layer was dried over anhydrous Na₂SO₄, filtered, and     concentrated. The residue was purified by column chromatography on     silica gel (EtoAc) to give tert-butyl     4-({2-chloro-5-[(dimethylamino)carbonyl]phenyl}sulfonyl)-1-piperazinecarboxylate     (258 mg, 71.1%).

-   (4) To a mixture of tert-butyl     4-({2-chloro-5-[(dimethylamino)carbonyl]phenyl}sulfonyl)-1-piperazinecarboxylate     (248 mg, 0.574 mmol) and 3,5-dimethylphenol (140 mg, 0.859 mmol) in     DMF (2 ml) was added t-BuOK (129 mg, 1.15 mmol) at room temperature.     This mixture was heated at 150° C. for two days. After cooling to     room temperature, ice water (10 ml) was added to the mixture. Two     phases were separated. The aqueous phase was extracted with CH₂Cl₂.     The combined organic layers were washed with aqueous NaHCO₃ and     brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. This     residue was purified by column chromatography on silica gel     (Hexane/EtoAc=1/2) to give tert-butyl     4-({2-(3,5-dichlorophenoxy)-5-[(dimethylamino)-carbonyl]phenyl}sulfonyl)-1-piperazinecarboxylate     (182 mg, 56.8%).

-   (5) To a solution of tert-butyl     4-({2-(3,5-dichlorophenoxy)-5-[(dimethylamino)carbonyl]phenyl}sulfonyl)-1-piperazinecarboxylate     (150 mg, 0.269 mmol) in CH₂Cl₂ was added 4M HCl solution in dioxane     (0.300 ml, 1.20 mmol) at 0° C. This mixture was stirred at room     temperature overnight. Solvents were removed by evaporation. The     resulting residue was suspended in Et₂O and collected by filtration     to give     4-(3,5-dichlorophenoxy)-N,N-dimethyl-3-(1-piperazinylsulfonyl)benzamide     hydrochloride (50.0 mg, 37.6%): mp 197-199° C.; HPLC-MS (ESI): Calcd     for C₁₉H₂₁Cl₂N₃O₄S [M+H]⁺ 458, Found: 458. -   Molecular weight: 494.8279 -   Activity grade RBA: B -   Activity grade Ca²⁺: B

In the similar manner as described in Example 10-1 above, compound in Example 10-2 as shown in Table 10 was synthesized.

TABLE 10 EX.No. molstructure MW M + 1 mp RBA Ca2+ 10-2

490.0443 454 242-247 B A

Example 11-1

-   (1) To a mixture of 5-fluoro-2-nitrotoluene (1.00 g, 6.45 mmol) in     CHCl₃ (10 ml) was added chlorosulfonic acid (0.86 ml, 12.9 mmol)     dropwise. The mixture was refluxed overnight. After the mixture was     cooled to room temperature, the mixture was diluted with CHCl₃, then     ice water was added to the mixture. The organic layer was extracted     with CHCl₃ and was washed with brine. The extracted organic layer     was dried over anhydrous MgSO₄, filtered, and concentrated in vacuo     to give a pale yellow oil.     -   The oil was dissolved in THF (50 ml). To the solution was added         tert-butyl 1-piperazinecarboxylate (1.20 g, 6.45 mmol), and         N,N-diisopropylethylamine (1.12 ml, 6.45 mmol) successively. The         mixture was stirred at room temperature for 4 hrs. The mixture         was concentrated in vacuo. The residue was diluted with         ethylacetate and was washed with brine. The organic layer was         dried over anhydrous MgSO₄, filtered, and concentrated in vacuo.         The residue was purified by column chromatography on silica gel         (EtoAc/Hexane) to give tert-butyl         4-[(2-fluoro-4-methyl-5-nitrophenyl)sulfonyl]-1-piperazinecarboxylate         (1.00 g, 38.4%) as a pale brown solid.

-   (2) To a solution of 3,5-dimethylphenol (33.3 mg, 0.27 mmol) in     1,4-dioxane (1 ml) was added sodium hydride (60% oil suspension,     11.9 mg, 0.30 mmol) portionwise. The mixture was stirred at room     temperature for 30 minutes. To the mixture was added a solution of     tert-butyl     4-[(2-fluoromethyl-5-nitrophenyl)sulfonyl]-1-piperazinecarboxylate     (100 mg, 0.25 mmol) in 1,4-dioxane (1 ml) slowly. The mixture was     stirred at 70° C. overnight. After the mixture was cooled to room     temperature, the mixture was concentrated in vacuo. The residue was     washed with ice water, then was dried in vacuo to give tert-butyl     4-{[2-(3,5-dimethylphenoxy)-4-methyl-5-nitrophenyl]sulfonyl}-1-piperazinecarboxylate     (92.8 mg, 74.1%) as a white solid.

-   (3) tert-butyl     4-{[2-(3,5-dimethylphenoxy)-4-methyl-5-nitrophenyl]sulfonyl}-1-piperazinecarboxylate     (186 mg, 0.368 mmol) was placed in a frame-dried two-necked flask.     It was dried in vacuo, then was purged with argon. To the flask was     added dry DMF, dimethylformamide dimethyl acetal (0.0585 ml, 0.441     mmol), and pyrrolidine 0.0369 ml, 0.441 mmol). The mixture was     stirred at 110° C. for 3 hrs. Additional pyrrolidine (0.0185 ml,     0.22 mmol) was added to the mixture. The mixture was stirred at     110° C. for additional 1 hr. After the mixture was cooled to room     temperature, the mixture was transferred to a solution of 4 M     aqueous ammonium acetate in DMF, using additional DMF to rinse the     mixture into the reaction flask To the solution was added 20% w/v     aqueous titanium(III) chloride (1.50 ml, 1.98 mmol) dropwise. The     suspension was stirred at room temperature for 15 minutes. The     mixture was made basic with 1N aqueous NaOH solution. The mixture     was diluted with diethylether. The mixture was filtered, then the     organic layer was extracted with diethylether, was washed with     brine, dried over anhydrous MgSO₄, filtered, and concentrated in     vacuo. The residue was purified by column chromatography on silica     gel (EtoAc/Hexane) to give tert-butyl     4-{[5-(3,5-dimethylphenoxy)-1H-indol-6-yl]sulfonyl}-1-piperazinecarboxylate     (42.2 mg, 23.6%) as a pale brown solid.

-   (4) To a solution of tert-butyl     4-{{[5-(3,5-dimethylphenoxy)-1H-indol-6-yl]-sulfonyl}-1-piperazinecarboxylate     (15.4 mg, 0.0317 mmol) in CH₂Cl₂ (1 ml) was added trifluoroacetic     acid (0.10 ml) at 0° C. The mixture was stirred at 0° C. for 2 hrs.     Toluene was added to the mixture, then was concentrated in vacuo.     The residue was triturated with diethylether to give     5-(3,5-dimethylphenoxy)-6-(1-piperazinylsulfonyl)-1H-indole     trifluoroacetate (12.7 mg, 80.2%).

HPLC-MS (ESI): Calcd for C₂₀H₂₃N₃O₃S [M+H]⁺ 368, Found: 368.

-   Molecular weight: 499.5129 -   Activity grade RBA: C -   Activity grade Ca²⁺: C

Example 12-1

-   (1) 4-Fluorobenzoic acid (5.0 g, 35.7 mmol) was added to     chlorosulfonic acid (31.5 g, 0.27 mol), and the mixture was stirred     at 150° C. for 2 hrs. After cooling to room temperature, the mixture     was poured into ice-water dropwise with cooling. The resulting white     precipitate was collected by filtration. The solid was washed with     water, and dried in vacuo to give 3-(chlorosulfonyl)-4-fluorobenzoic     acid (6.33 g, 74.3%).

-   (2) To a solution of 3-(chlorosulfonyl)-4-fluorobenzoic acid (1.0 g,     4.19 mmol) in THF (10 ml) was added N-tert-butyl     1-homopiperazinecarboxylate (0.92 g, 4.61 mmol) in THF (5 ml)     dropwise at 0° C., followed by Et₃N (1.08 ml, 6.28 mmol). The     mixture was stirred at room temperature for 6 hrs. After quenched by     water, the solvent was removed by evaporation. The resulting residue     was dissolved in 1N NaOH (24 ml), and washed with Et₂O two times.     Then the aqueous layer was acidified to pH 3-4 by 1N HCl, then     extracted with EtOAc 3 times. The organic layer was dried over     anhydrous Na₂SO₄, the solvent was evaporated in vacuo to give     3-{[4-(tert-butoxycarbonyl)-1,4-diazepan-1-yl]sulfonyl}-4-fluorobenzoic     acid as a colorless form (1.12 g, 66.4%):

-   (3) To a solution of     3-{[4-(tert-butoxycarbonyl)-1,4-diazepan-1-yl]sulfonyl}-4-fluorobenzoic     acid (250 g, 0.62 mol) in THF (2000 ml) was added CDI (125 g, 0.77     mol) at 0° C. under Ar. The mixture was stirred at 0° C. for 1 hr.     Then NH₃ gas was bubbled into the mixture for 2 hrs. White     precipitate was filtered off, and the filtrate was extracted with     EtOAc, washed with 1N HCl, and sat. NaHCO₃ solution, and brine. The     organic extracts were dried over anhydrous Na₂SO₄, the solvent was     evaporated in vacuo to give tert-butyl     4-{[5-(aminocarbonyl)-2-fluorophenyl]sulfonyl}-1,4-diazepane-1-carboxylate     as a white solid (240 g, 96.2%)

-   (4) To a solution of tert-butyl     4-{[5-(aminocarbonyl)-2-fluorophenyl]sulfonyl}-1,4-diazepane-1-carboxylate     (5.0 g, 12.5 mmol) in dry CH₂Cl₂ (150 ml) was added Et₃N (6.94 ml,     49.8 mmol) under Ar. Then the solution was cooled to −5° C. (dry     ice/i-PrOH). (CF₃SO₂)₂O (3.14 ml, 18.7 mmol) was added to the     mixture dropwise, cooling under 5° C. After 1.5 hrs, the reaction     was quenched by water, then extracted with CH₂Cl₂, and washed with     water and brine. The organic extract was dried over anhydrous     Na₂SO₄. The solvent was evaporated in vacuo. The resulting residue     was purified by column chromatography on silica-gel     (Hexane/EtoAc=1/1) to give tert-butyl     4-[(5-cyano-2-fluorophenyl)sulfonyl]-1,4-diazepane-1-carboxylate as     a brown oil (4.12 g, 86.3%)

-   (5) To a solution of tert-butyl     4-[(5-cyano-2-fluorophenyl)sulfonyl]-1,4-diazepane-1-carboxylate     (4.12 g, 10.75 mmol) and 3,5-dichlorophenol (5.25 g, 32.2 mmol) in     dioxane (100 ml) was added NaH (1.54 g, 37.6 mmol). The mixture was     stirred under reflux for 1 hr. After cooled to room temperature, the     mixture was quenched by water, and extracted with CH₂Cl₂ and washed     with 1N NaOH, and brine. The organic extract was dried over     anhydrous Na₂SO₄, the solvent was evaporated in vacuo. The resulting     residue was purified by column chromatography on silica-gel     (Hexane/EtoAc=1/1) to give tert-butyl     4-{[5-cyano-2-(3,5-dichlorophenoxy)phenyl]sulfonyl}-1,4-diazepane-1-carboxylate     as a white solid (3.08 g, 54.5%)

-   (6) To a solution of tert-butyl     4-{[5-cyano-2-(3,5-dichlorophenoxy)phenyl]-sulfonyl}-1,4-diazepane-1-carboxylate     (3.1 g, 5.89 mmol) in CH₂Cl₂ (60 ml) was added 4N HCl in dioxane (60     ml). The mixture was stirred at room temperature for 2 hrs. After     the solvent was removed by evaporation, the resulting white solid     was washed with CH₃CN to give     3-(1,4-diazepan-1-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile     hydrochloride as a white solid (2.13 g, 78.2%): mp 278-280° C.; ¹H     NMR (500 MHz, DMSO-d₆) δ 1.99-2.02 (2H, m), 3.19-3.24 (4H, m),     3.41-3.43 (2H, m), 3.64-3.66 (2H, m), 7.29 (1H, d, J=8.5 Hz), 7.41     (2H, m), 7.59 (1H, m), 8.12 (1H, dd, J=2.2, 8.8 Hz), 8.30 (1H, d,     J=1.9 Hz), 8.99 (1H, br); HPLC-MS (ESI): Calcd for C₁₈H₁₈Cl₃N₃O₃S     [M+H]⁺ 426 and 428, found: 426 and 428. -   Molecular weight: 462.785 -   IC₅₀ (CCR3): 35 μM -   IC₅₀ (Ca²⁺): 20 μM

IC₅₀ (Chemotaxis): 8 μM

In the similar manner as described in Example 12-1 above, compounds in Example 12-2 and 12-3 as shown in Table 12 were synthesized.

TABLE 12 EX.No. molstructure MW M + 1 mp RBA Ca2+ 12-2

442.36752 447 253 B 12-3

483.2034 486 261 B

Example 13-1

-   (1) To a mixture of 4-fluoro-3-nitrobenzoic acid (10.00 g, 54.02     mmol) and 3,5-dichlorophenol (13.21 g, 81.03 mmol) in THF (300 ml)     was added NaH (5.40 g, 135.05 mmol) at room temperature. The     resulting mixture was heated to 70° C. After 2 hrs, the reaction     mixture was poured into water and 6N HCl (15 ml) was added. The     resulting mixture was extracted with EtOAc. The extract was washed     with brine, and dried over MgSO₄, the solvent was evaporated in     vacuo. The residue was collected by filtration and washed with     hexane to give 4-(3,5-dichlorophenoxy)-3-nitrobenzoic acid as a     slight yellow powder (15.29 g 86.3%).

-   (2) To a cooled solution of 4-(3,5-dichlorophenoxy)-3-nitrobenzoic     acid (15.29 g, 46.60 mmol) in THF (300 ml), was added CDI (11.33 g,     69.90 mmol) and resulting mixture was allowed to warm to room     temperature. After 2 hrs, the mixture was cooled with ice-bath and     then NH₃ gas was introduced directly into the reaction mixture.     After 2 hrs, the reaction mixture was condensed under reduce     pressure. The residue was dissolved in water and the resulting     mixture was extracted with EtOAc. The extract was washed with 1N     NaOH, 1N HCl, and brine, dried over MgSO₄. The solvent was     evaporated in vacuo. The crude product was collected by filtration     and washed with MeCN to give     4-(3,5-dichlorophenoxy)-3-nitrobenzamide as a white powder (15.72 g,     quantitative).

-   (3) The solution of 4-(3,5-dichlorophenoxy)-3-nitrobenzamide (15.50     g, 47.38 mmol) and i-Pr₂EtN (49.52 ml, 284.30 mmol) in CH₂Cl₂     (500 ml) was cooled to −5° C. with dry-ice/1-PrOH bath. Tf₂O (16.04     ml, 94.77 mmol) was added dropwise to the mixture below 0° C. and     then additional i-Pr₂EtN (24.76 ml, 142.15 mmol) and Tf₂O (12.03 ml,     71.08 mmol) was added. The mixture was stirred at 0° C. for 30 min.     Water was added into the reaction mixture and the resulting mixture     was condensed under reduced pressure. The obtained residue was     partitioned between water and EtOAc and the resulting mixture was     extracted with EtOAc. The extract was washed with 1N HCl and brine,     dried over MgSO₄ The solvent was evaporated in vacuo. The residue     was purified by column chromatography on silica-gel     (CHCl₃/EtoAc=100/0 to 95/5) to give     5-cyano-2-(3,5-dichlorophenoxy)nitrobenzene as a white powder (4.08     g, 27.9%).

-   (4) The mixture of 5-cyano-2-(3,5-dichlorophenoxy)nitrobenzene (4.08     g, 13.20 mmol) and Tin(II) chloride dihydrate (17.87 g, 79.20 mmol)     in EtOAc (200 ml) was heated to reflux for 3 hrs. After cooled to     room temperature, the reaction mixture was poured into sat. NaHCO₃.     The mixture was extracted with EtOAc. The extract was washed with     brine, and dried over MgSO₄. The solvent was evaporated in vacuo to     give 5-cyano-2-(3,5-dichlorophenoxy)aniline (3.53 g, 95.8%).

-   (5) 5-Cyano-2-(3,5-dichlorophenoxy)aniline (3.53 g, 12.65 mmol) was     dissolved in the mixture of conc. HCl (6.33 ml) and AcOH 2.53 ml).     The solution was cooled to 0° C. and sodium nitrite (0.96 g, 13.91     mmol) in water (1.27 ml) was added dropwise with stirring. After 30     min, the reaction mixture was added dropwise to the suspended     mixture of CuCl (0.63 g, 6.32 mmol) in saturated solution of SO₂ in     AcOH (25.32 ml) at 5° C. The reaction mixture was stirred at 10° C.     for 30 min. poured into water and the resulting mixture was     extracted with EtOAc. The extract was washed with sat. NaHCO₃,     brine, and dried over MgSO4. The solvent was evaporated in vacuo to     give 5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonylchloride as a     brown powder (4.45 g, 97%).

-   (6) To a solution of     5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonylchloride (0.03 g 0.08     mmol) in THF (1 ml), (3S)-(tert-butoxycarbonylamino)pyrrolidine     (0.05 g, 0.25 mmol) was added. The reaction mixture was stirred at     room temperature overnight, then poured into water and the resulting     mixture was extracted with EtOAc. The extract was washed with brine,     and dried over MgSO4. The solvent was evaporated in vacuo. The     residue was purified by preparative TLC on silica gel     (CH₂Cl₂/CH₃OH=25/1) to give     1-{5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl}-(3S)-(tert-butoxycarbonylamino)pyrrolidine     as an oil (0.02 g, 47%).

-   (7) To the solution of     1-{5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl}-(3S)(tert-butoxycarbonylamino)pyrrolidine     (0.03 g, 0.04 mmol) in 1,4-dioxane (1 ml) was added 4N HCl (1 ml) in     1,4-dioxane. The reaction mixture was stirred at room temperature     overnight. The solvent was evaporated in vacuo. The obtained residue     was dissolved in THF followed by addition of ether. The produced     precipitate was collected by filtration, washed with ether and dried     in vacuo to give     1-{5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl}-(3S)aminopyrrolidine     hydrocloride as a white powder (13.4 mg, 77%): mp 276° C.; ¹H NMR     (500 MHz, DMSO-d₆) δ 1.92-1.97 (1H, m), 2.15-2.22 (1H, m), 3.34-3.41     (2H, m), 3.51-3.56 (1H, m), 3.63-3.67 (1H, m), 3.79-3.83 (1H, m),     7.34 (1H, d, J=8.8 Hz), 7.39 (2H, dd, J=1.6, 1.9 Hz), 8.13 (1H, dd,     J=8.5, 2.2 Hz), 8.21 (3H, br), 8.29 (1H, d, J=1.9); HPLC-MS (ESI):     calcd for C₁₇H₁₅Cl₂N₃O₃S [M+H]⁺ 411 and 413, Found: 411 and 413. -   Molecular weight: 448.758 -   Activity grade Ca²⁺: A

In the similar manner as described in Example 13-1 above, compounds in Example 13-2 to 13-12 as shown in Table 13 were synthesized.

TABLE 13 EX.No. molstructure MW M + 1 mp RBA Ca2+ 13-2

542.4886 542 90-93 B B 13-3

480.41691 480 144-145 A 13-4

424.30855 424 311–312 A A 13-5

452.36273 452 163-165 B A 13-6

452.36273 452 164-165 30 40 + G9 13-7

520.86613 483 240 A A 13-8

422.72013 426 214 A 13-9

492.76832 457 262  7 12 + G12  13-10

470.76473 434 104 A  13-11

466.38982 467 13 8  13-12

452.36273 452 161 A

Example 14-1

-   (1) To a cold (10° C.) solution of     3-{[4-(tert-butoxycarbonyl)-1-piperazinyl]-sulfonyl}-4-fluorobenzoic     acid (0.200 g, 0.515 mmol) and 3,5-dimethylphenol (0.063 g, 0.515     mmol) in 1,4-dioxane (1.0 ml) was added NaH (0.041 g, 1.030 mmol),     and the stirring was continued for 15 min. The mixture was heated at     120° C. for 3 hrs. N-Methyl-2-pyrollidone (1.0 ml) was added to the     mixture, which was then heated at 120° C. overnight. After cooled to     room temperature, the mixture was quenched with water and then     extracted with a 1:1 mixture of EtOAc and hexane. The aqueous phase     was separated, and the organic phase was extracted with water. The     combined aqueous phase was acidified to pH 3-4 with 1N HCl, and then     extracted with EtOAc. The separated organic phase was washed with     water and brine, dried over Na₂SO₄. The solvent was evaporated in     vacuo. The residue was suspended in boiled MeOH for 1 h. After     cooling to room temperature, the precipitate was collected by     filtration, washed with MeOH and dried in vacuo to give     3-{[4-(tert-butoxycarbonyl)-1-piperazinyl]sulfonyl}-4-(3,5-dimethylphenoxy)benzoic     acid (0.101 g, 40.0%): HPLC-MS (ESI): Calcd for C₂₄H₃₀N₂O₇S [M+H]⁺     491, Found: 391(−Boc)

-   (2) To a solution of     3-{[4-(tert-butoxycarbonyl)-1-piperazinyl]sulfonyl}-4-(3,5-dimethylphenoxy)benzoic     acid (0.030 g, 0.061 mmol) in 1,4-dioxane (0.5 ml) was added 4N HCl     in 1,4-dioxane (1.5 ml). The mixture was further stirred at room     temperature for 3 hrs, and then concentrated in vacuo. The residue     was washed twice with CH₃CN and dried in vacuo to give     4-(3,5-dimethylphenoxy)-3-(1-piperazinylsulfonyl)benzoic acid     hydrochloride (0.027 g, quantitative): ¹H NMR (500 MHz, DMSO-d₆) δ     2.31 (6H, s), 3.17 (4H, br), 3.47 (4H, br), 6.87 (1H, s), 6.96 (1H,     s), 6.98 (1H, br), 8.15 (1H, dd, J=2.2, 8.8 Hz), 8.39 (1H, d, J=2.2     Hz), 9.19 (1H, br), 13.36 (1H, br); HPLC-MS (ES): Calcd for     C₁₉H₂₂N₂O₅S [M+H]⁺ 391, Found: 391. -   Molecular weight: 426.922 -   Activity grade Ca²⁺:A -   In the similar manner as described in Example 14-1 above, compounds     in Example 14-2 to 14-4 as shown in Table 14 were synthesized.

TABLE 14 EX.No. molstructure MW M + 1 mp RBA Ca2+ 14-2

490.5799 391 222 A 14-3

467.75844 431 >260 A 14-4

487.72433 466 307 B

Example 15-1

-   (1) To a solution of     3-{[4-(tert-butoxycarbonyl)-1-piperazinyl]sulfonyl}-4-(3,5-dimethylphenoxy)benzoic     acid (0.100 g, 0.204 mmol) in THF (1.0 ml) was added     1,1′-carbonylimidazole (0.041 g, 0.255 mmol), and the mixture was     stirred at room temperature. After 3 hrs, 0.5M NH₃ in 1,4-dioxane     was added, and the stirring was continued overnight. The resultant     mixture was concentrated in vacuo, and the residue was partitioned     between EtOAc and saturated NaHCO₃. The separated organic phase was     washed with water and brine, dried over Na₂SO₄. The solvent was     evaporated in vacuo. The solid obtained was washed with EtOH and     dried in vacuo to give tert-butyl     4-{[5-(aminocarbonyl)-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-1-piperazinecarboxylate     (0.071 g, 71.1%).

-   (2) To a suspension of tert-butyl     4-{[5-(aminocarbonyl)-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-1-piperazinecarboxylate     (0.057 g, 0.116 mmol) in 1,4-dioxane (1.0 ml) was added 4N HCl in     1,4-dioxane (3.0 ml), and the mixture was stirred at room     temperature for 2 hrs. The mixture was concentrated in vacuo, washed     twice with CH₃CN and dried in vacuo to give     4-(3,5-dimethylphenoxy)-3-(1-piperazinylsulfonyl)benzamide     hydrochloride (0.047 g, 94.8%): ¹H NMR (500 MHz, DMSO-d₆) δ 2.30     (6H, s), 3.16 (4H, br), 3.45 (4H, br), 6.83 (1H, s), 6.94 (1H, s),     6.95 (1H, d, J=8.8 Hz), 7.51 (1H, s), 8.11 (1H, dd, J=2.2, 8.5 Hz),     8.18 (1H, s), 8.37 (1H, d, J=2.2 Hz), 9.22 (2H, s); HPLC-MS (ESI):     Calcd for C₁₉H₂₃N₃O₄S [M+H]⁺ 390, Found: 390. -   Molecular weight: 425.937 -   Activity grade RBA: -   Activity grade Ca²⁺: A

Example 15-2

-   (1) To a mixture of     3-{[4-(tert-butoxycarbonyl)-1-piperazinyl]sulfonyl}-4-(3,5-dimethylphenoxy)benzoic     acid (0.300 g, 0.612 mmol), K₂CO₃, (0.169 g, 1.223 mmol) and DMF     (3.0 ml) was added MeI (0.174 g, 1.223 mmol), and the stirring was     continued at room temperature overnight. The mixture was quenched     with water, and extracted with EtOAc. The separated organic phase     was washed with water and brine, dried over Na₂SO₄. The solvent was     evaporated in vacuo, The residue was recrystallized from MeOH to     give tert-butyl     4-{[2-(3,5-dimethylphenoxy)-5-(methoxycarbonyl)phenyl]sulfonyl}-1-piperazinecarboxylate     (0.276 g, 89%).

-   (2) To a suspension of tert-butyl     4-{[2-(3,5-dimethylphenoxy)-5-(methoxycarbonyl)phenyl]sulfonyl}-1-piperazinecarboxylate     (0.030 g, 0.059 mmol) in 1,4-dioxane (1.0 ml) was added 4N HCl in     1,4-dioxane (3.0 ml). The resulting clear solution was stirred at     room temperature for 3 hrs. The mixture was concentrated in vacuo,     washed twice with Et₂O and dried in vacuo to give methyl     4-(3,5-dimethylphenoxy)-3-(1-piperazinylsulfonyl)benzoate     hydrochloride (0.027 g, quantative): mp 120° C.; ¹H NMR (500 MHz,     DMSO-d₆) δ 2.31 (6H, s), 3.16 (4H, br), 3.48 (4H, br), 3.88 (3H, s),     6.89 (2H, s), 6.97 (1H, d, J=2.3 Hz), 6.98 (1H, s), 8.17 (2H, dd,     J=2.3, 9.0 Hz), 8.40 (1H, d, J=2.3 Hz), 9.22 (2H, br); HPLC-MS (ES):     Calcd for C₂₀H₂₄N₂O₅S [M+H]+405, Found: 405. -   Molecular weight: 440.949 -   Activity grade Ca²⁺: A -   In the similar manner as described in Example 15-1 or 15-2 above,     compounds in Example 15-3 and 15-4 as shown in Table 15 were     synthesized.

TABLE 15 EX.No. molstructure MW M + 1 mp RBA Ca2+ 15-3

460.38286 424 161 B 15-4

484.76414 488 >300 B

Example 16-1

-   (1) To a cold (0° C.) solution of     4-{[2-(3,5-dimethylphenoxy)-5-(methoxycarbonyl)phenyl]sulfonyl}-1-piperazinecarboxylate     (0.227 g, 0.450 mmol) in THF (3.0 ml) was added LiBH₄ (0.012 g,     0.540 mmol). The mixture was stirred at room temperature for 3 hrs,     and at 60° C. for 4 hrs. After cooled to room temperature, the     mixture was quenched with saturated NH₄Cl, and extracted with EtOAc.     The separated organic phase was washed with water and brine, dried     over Na₂SO₄. The solvent was evaporated in vacuo. The residue was     purified by recrystallization from CH₃CN to give tert-butyl     4-{[2-(3,5-dimethylphenoxy)-5-(hydroxymethyl)phenyl]sulfonyl}-1-piperazinecarboxylate     (0.156 g, 72.8%).

-   (2) To a solution of tert-butyl     4-{[2-(3,5-dimethylphenoxy)-5-(hydroxymethyl)phenyl]sulfonyl}-1-piperazinecarboxylate     (0.027 g, 0.057 mmol) in 1,4-dioxane (1.0 ml) was added 4N HCl in     1,4-dioxane (3.0 ml). The mixture was stirred at room temperature     for 3 hrs. The mixture was concentrated in vacuo, washed twice with     Et₂O and dried in vacuo to give     [4-(3,5-dimethylphenoxy)-3-(1-piperazinylsulfonyl)phenyl]methanol     hydrochloride (0.020 g, 85.5%): mp 160° C. ¹H NMR (500 MHz, DMSO-d₆)     δ 2.27 (6H, s), 3.14 (4H, br), 3.39 (4H, br), 4.53 (2H, d, J=5.7     Hz), 5.42 (1H, t, J=5.7 Hz), 6.71 (2H, s), 6.86 (1H, s), 6.96 (1H,     d, J=8.5 Hz), 7.57 (1H, dd, J=2.2, 8.5 Hz), 7.83 (1H, d, J=1.9 Hz),     9.12 (2H, br); HPLC-MS (ESI): Calcd for C₁₉H₂₄N₂O₄S [M+H]⁺ 377,     Found: 377. -   Molecular weight: 412.939 -   Activity grade Ca²⁺: A

Example 17-1

-   (1) To a stirred suspension of NaH (60%, 0.015 g, 0.375 mmol) in     1,4-dioxane (2.0 ml) was added 3,5-dichlorothiophenol (0.067 g,     0.374 mmol). After 15 min, tert-butyl     4-[(5-cyano-2-fluorophenyl)sulfonyl]-1-piperazinecarboxylate (0.100     g, 0.271 mmol) was added, and the suspension was stirred at room     temperature for 10 min. THF (0.5 ml) was added, and the stirring was     continued for 2 hrs. The mixture was quenched with water, and     extracted with EtOAc and saturated aqueous NaHCO₃ solution. The     separated organic phase was washed with water and brine, dried over     Na₂SO₄. The solvent was evaporated in vacuo. The residue was     recrystallized from CH₃CN to give tert-butyl     4-({5-cyano-2-[(3,5-dichlorophenyl)sulfanyl]phenyl}sulfonyl)-1-piperazinecarboxylate     (0.088 g, 61.5%).

-   (2) To a solution of tert-butyl     4-({5-cyano-2-[(3,5-dichlorophenyl)sulfanyl]-phenyl}sulfonyl)-1-piperazinecarboxylate     (0.020 g, 0.038 mmol) in 1,4-dioxane (1.0 ml) was added 4N HCl in     1,4-dioxane (3.0 ml), and the stirring was continued for 3 hrs. The     mixture was concentrated in vacuo. The residue was recrystallized     from diisopropylether. The solid obtained was washed with     diisopropylether, dried in vacuo to give     4-[(3,5-dichlorophenyl)sulfanyl]-3-(1-piperazinylsulfonyl)benzonitrile     hydrochloride (0.017 g, 96.6%): mp 82° C. ¹H NMR (500 MHz, DMSO-d₆)     δ 3.19 (4H, br), 3.53 (4H, br), 7.18 (1H, d, J=8.5 Hz), 7.73 (1H, d,     J=1.9 Hz), 7.87 (1H, t, J=1.9 Hz), 7.97 (1H, dd, J=1.3, 8.5 Hz), 8.3     (1H, d, J=1.6 Hz), 8.99 (2H, br); HPLC-MS (ESI): Calcd for     C₁₇H₁₅Cl₂N₃O₂S₂ [M+H]⁺ 428, Found: 428. -   Molecular weight: 464.823 -   IC₅₀ (CCR3): 3 μM -   IC₅₀ (Ca²⁺): 2 μM -   IC₅₀ (Chemotaxis): 2 μM

In the similar manner as described in Example 17-1 above, compounds in Example 17-2 and 17-3 as shown in Table 17 were synthesized.

TABLE 17 EX. No. moistructure MW M + 1 mp RBA Ca2+ 17-2

516.53436 516 124 A 17-3

478.85006 442 277-278 3 1

Example 18-1

-   (1) To a stirred mixture of tert-butyl     4-({5-cyano-2-[(3,5-dichlorophenyl)sulfanyl]phenyl}sulfonyl)-1-piperazinecarboxylate     (0.011 g, 0.020 mmol), CCl₄ (0.4 ml), CH₃CN (0.4 ml) and water     (0.8 ml) was added NaIO₄ (0.030 g, 0.142 mmol) followed by RuCl₃     (0.003 g, 0.014 mmol). The mixture was stirred at room temperature     for 4 hrs. The mixture was partitioned between EtOAc and water. The     separated organic phase was washed with saturated aqueous NaHCO₃     solution and brine, dried over Na₂SO₄. The solvent was evaporated in     vacuo. The residue was dissolved in hot CH₃CN, and allowed to cool     to room temperature. The precipitate was collected by filtration,     washed with CH₃CN, and dried in vacuo to give tert-butyl     4-({5-cyano-2-[(3,5-dichlorophenyl)sulfonyl]phenyl}sulfonyl)-1-piperazinecarboxylate     (0.016 g, 60.3%).

-   (2) To a suspension of tert-butyl     4-({5-cyano-2-[(3,5-dichlorophenyl)sulfonyl]-phenyl}sulfonyl)-1-piperazinecarboxylate     (0.011 g) in 1,4-dioxane (0.5 ml) was added 4N HCl in 1,4-dioxane     (1.5 ml), and the stirring was continued for 3 hrs. The mixture was     concentrated in vacuo, and recrystallized with diisopropylether. The     obtained solid was washed with diisopropylether, and dried in vacuo     to give     4-[(3,5-dichlorophenyl)sulfonyl]-3-(1-piperazinylsulfonyl)benzonitrile     hydrochloride (0.008 g, 82%): mp 258° C. ¹H NMR (500 MHz, DMSO-d₆) δ     3.15 (4H, br), 3.57 (4H, br), 7.94 (2H, d, J=1.9 Hz), 8.05 (1H, t,     J=1.9 Hz), 8.52-8.55 (2H, m), 8.72 (1H, d, J=8.5 Hz), 8.96 (2H, br);     FAB-MS: Calcd for C₁₇H₁₅Cl₂N₃O₄S₂ [M+H]⁺ 460, Found: 460. -   Molecular weight: 496.821 -   IC₅₀ (CCR3): 1.2 μM -   IC₅₀ (Ca²⁺): 7 μM

Example 19-1

-   (1) To a cold (0° C.) solution of tert-butyl     4-({5-cyano-2-[(3,5-dichlorophenyl)sulfanyl]phenyl}sulfonyl)-1-piperazinecarboxylate     (0.022 g, 0.042 mmol) in CH₂Cl₂ (0.6 ml) was added     m-chloroperbenzoic acid (0.022 g, 0.062 mmol), and the stirring was     continued for 1 h. The mixture was allowed to warm to room     temperature, and stirred for 30 min. The mixture was quenched with     10% Na₂SO₃ solution, and extracted with EtOAc. The extract was     washed with saturated NaHCO₃, water and brine, dried over Na₂SO₄.     The solvent was evaporated in vacuo. The solid obtained was washed     twice with MeOH and dried in vacuo to give tert-butyl     4-({5-cyano-2-[(3,5-dichlorophenyl)sulfinyl]-phenyl}sulfonyl)-1-piperazinecarboxylate     (0.022 g, 97.1%).

-   (2) To a suspension of tert-butyl     4-({5-cyano-2-[(3,5-dichlorophenyl)sulfinyl]-phenyl}sulfonyl)-1-piperazinecarboxylate     (0.017 g, 0.031 mmol) in 1,4-dioxane (1.0 ml) was added 4N HCl in     1,4-dioxane (3.0 ml). The mixture was stirred at room temperature     for 3 hrs, and then concentrated in vacuo. The residue was washed     twice with CH₃CN, and dried in vacuo to give     4-[(3,5-dichlorophenyl)sulfinyl]-3-(1-piperazinylsulfonyl)benzonitrile     hydrochloride (0.008 g, 53.3%): mp 219° C. ¹H NMR (500 MHz, DMSO-d₆)     (3.20-3.24 (4H, m), 3.43-3.46 (4H, m), 7.74 (1H, d, J=1.9 Hz), 7.85     (1H, t, J=1.9 Hz), 8.42 (1H, d, J=1.6 Hz), 8.47 (1H, dd, J=1.6, 8.2     Hz), 8.52 (1H, d, J=8.2 Hz), 8.87 (2H, br); FAB-MS: Calcd for     C₁₇H₁₅Cl₂N₃O₃S₂ [M+H]⁺ 444, Found: 444. -   Molecular weight: 480.822 -   Activity grade Ca²⁺: B

Example 20-1

-   (1) A solution of tert-butyl     4-[(5-cyano-2-fluorophenyl)sulfonyl]-1-piperazinecarboxylate (0.100     g, 0.271 mmol) in THF (2.0 ml) was cooled with a water bath, and     KOtBu (0.033 g, 0.298 mmol) was added with stirring. The mixture was     heated at reflux for 7 hrs. After cooled to room temperature, KOtBu     (0.030 g, 0.267 mmol) was added, and the mixture was heated at     reflux overnight. After cooled to room temperature, the mixture was     quenched with saturated NH₄Cl, and extracted with EtOAc. The     separated organic phase was washed with water and brine, dried over     Na₂SO₄. The solvent was evaporated in vacuo. The residue was     purified by column chromatography on silica gel (Hexane/EtOAc=4/1).     The product obtained was suspended in hexane including a small     amount of EtOAc, collected by filtration, washed with hexane     including a small amount of EtOAc, and dried in vacuo to give     tert-butyl     4-({5-cyano-2-[(3,5-dichlorophenyl)amino]phenyl}sulfonyl)-1-piperazinecarboxylate     (0.087 g, 62.8%).

-   (2) To a solution of tert-butyl     4-({5-cyano-2-[(3,5-dichlorophenyl)amino]-phenyl}sulfonyl)-1-piperazinecarboxylate     (0.035 g, 0.068 mmol) in 1,4-dioxane (0.5 ml) was added 4N HCl in     1,4-dioxane (1.5 ml), and the stirring was continued for 3 hrs. The     mixture was concentrated in vacuo. The residue was crystallized from     CH₃CN, washed with CH₃CN, and dried in vacuo to give     4-[(3,5-dichlorophenyl)amino]-3-(1-piperazinylsulfonyl)benzonitrile     hydrochloride (0.030 g, 97.9%): ¹H NMR (500 MHz, DMSO-d₆) δ     3.13-3.16 (4H, m), 3.34-3.37 (4H, m), 7.37 (1H, d, J=8.8 Hz),     7.39-7.41 (1H, m), 7.41 (2H, s), 7.93 (1H, dd, J=2.2, 8.8 Hz), 8.13     (1H, d, J=2.2 Hz), 8.41 (1H, s), 8.87 (2H, br); FAB-MS: Calcd for     C₁₇H₁₆Cl₂N₄O₂S [M+H]⁺ 411, Found: 411. -   Molecular weight: 447.773 -   Activity grade RBA: A -   Activity grade Ca²⁺: A

Example 21-1

-   (1) To a cold (0° C.) solution of tert-butyl     4-({5-cyano-2-[(3,5-dichlorophenyl)amino]phenyl}sulfonyl)-1-piperazinecarboxylate     (0.049 g, 0.096 mmol) in DMF (1.5 ml) including MeI (0.041 g, 0.287     mmol) was added NaH (0.005 g, 0.115 mmol), and the stirring was     continued for 1 h. The mixture was allowed to warm to room     temperature, and the stirred was continued for 2 hrs. The mixture     was cooled with ice-water bath, quenched with saturated NH₄Cl     solution, and extracted with EtOAc and water. The separated organic     phase was washed with brine, dried over Na₂SO₄. The solvent was     evaporated in vacuo. The residue was purified by column     chromatography on silica gel (Hexane/EtOAc=4/1) to give tert-butyl     4-({5-cyano-2-[(3,5-dichlorophenyl)(methyl)amino]phenyl}sulfonyl)-1-piperazinecarboxylate     (0.048 g, 95.3%).

-   (2) To a suspension of tert-butyl     4-({5-cyano-2-[(3,5-dichlorophenyl)(methyl)amino]phenyl}sulfonyl)-1-piperazinecarboxylate     (0.043 g, 0.082 mmol) in 1,4-dioxane (1.0 ml) was added 4N HCl in     1,4-dioxane (3.0 ml). The mixture was stirred at room temperature     for 2 hrs, and then concentrated in vacuo. The residue was washed     twice with Et₂O, and dried in vacuo to give     4-[(3,5-dichlorophenyl)(methyl)amino]-3-(1-piperazinylsulfonyl)benzonitrile     hydrochloride (0.037 g, 97.9%): mp 163° C. ¹H NMR (500 MHz, DMSO-d₆)     δ 2.98 (4H, br), 3.18 (3H, s), 3.29 (4H, br), 6.53 (2H, d, J=1.6     Hz), 6.97 (1H, t, J=1.6 Hz), 7.71 (1H, d, J=8.2 Hz), 8.31 (1H, dd,     J=2.2, 8.2 Hz), 8.39 (1H, d, J=1.9 Hz), 8.92 (2H, br); FAB-MS: Calcd     for C₁₈H₁₈Cl₂N₄O₂S [M+H]⁺ 425, Found: -   Molecular weight: 461.800 -   Activity grade Ca²⁺: B

In the similar manner as described in Example 21-1 above, compounds in Example 21-2 as shown in Table 21 were synthesized.

TABLE 21 EX. No. moistructure MW M + 1 mp RBA Ca2+ 21-2

440.9525 405 243 A

Example 22-1

-   (1) To a cold (0° C.) mixture of     3-{[4-(tert-butoxycarbonyl)-1-piperazinyl]sulfonyl}-4-(3,5-dimethylphenoxy)benzoic     acid (0.450 g, 0.917 mmol), 3-aminopropionitrile (0.072 g, 1.009     mmol), HOBt (0.186 g, 1.376 mmol) and DMF (5.0 ml) was added     1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.211     g, 1.101 mmol). After 15 min, the mixture was allowed to warm to     room temperature, and the stirring was continued overnight. The     mixture was partitioned between EtOAc and water. The separated     organic phase was washed with saturated NaHCO₃ solution, water and     brine, dried over Na₂SO₄. The solvent was evaporated in vacuo. The     residue was purified by column chromatography on silica gel     (Hexane/EtOAc=1/2) to give tert-butyl     4-{[5-{[(2-cyanoethyl)amino]carbonyl}-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-1-piperazinecarboxylate     (0.490 g, 98.4%).

-   (2) To a solution of tert-butyl     4-{[5-{[(2-cyanoethyl)amino]carbonyl}-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-1-piperazinecarboxylate     (0.030 g, 0.055 mmol) in 1,4-dioxane (1.0 ml) was added 4N HCl in     1,1-dioxane (3.0 ml). The mixture was stirred at room temperature     for 1.5 hrs, and then concentrated in vacuo. The residue was     crystallized from Et₂O, washed with Et₂O and dried in vacuo to give     N-(2-cyanoethyl)-4-(3,5-dimethylphenoxy)-3-(1-piperazinylsulfonyl)benzamide     hydrochloride (0.025 g, 94.4%): mp 101° C. ¹H NMR (500 MHz, DMSO-d₆)     δ 2.30 (6H, s), 2.79 (2H, t, J=6.4 Hz), 3.14-3.18 (4H, m), 3.42-3.45     (4H, m), 3.47-3.54 (2H, m), 6.82 (2H, s), 6.95 (1H, s), 7.02 (1H, d,     J=8.7 Hz), 8.10 (1H, dd, J=2.3, 8.7 Hz), 8.38 (1H, d, J=2.3 Hz),     9.02 (2H, br), 9.84 (1H, t, J=6.0 Hz); HPLC-MS (ESI): Calcd for     C₂₂H₂₆N₄O₄S [M+H]⁺ 443, Found: 443. -   Molecular weight: 479.001 -   Activity grade Ca²⁺: A

Example 22-2

-   (1) A mixture of tert-butyl     4-([5-{[(2-cyanoethyl)amino]carbonyl}-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-1-piperazinecarboxylate     (0.040 g, 0.074 mmol) and 4 N HCl in 1,4-dioxane (3.0 ml) was     stirred for 1.5 hrs. 5N HCl was added, and the stirring was     continued for 3 days. The mixture was concentrated in vacuo, and the     residue was recrystallized from CH₃CN. The solid obtained was washed     twice with CH₃CN and dried in vacuo to give     N-[4-(3,5-dimethylphenoxy)-3-(1-piperazinylsulfonyl)benzoyl]-beta-alanineamide     hydrochloride (0.036 g, 98.3%): mp 121° C. ¹H NMR (500 MHz, DMSO-d₆)     δ 2.30 (6H, s), 2.36 (2H, t, J=7.3 Hz), 3.16 (4H, br), 3.42-3.46     (6H, m), 6.81 (2H, s), 6.83 (1H, s), 6.94 (1H, s), 6.98 (1H, d,     J=8.5 Hz), 7.36 (1H, s), 8.08 (1H, dd, J=2.2, 8.8 Hz), 8.35 (1H, d,     J=2.2 Hz), 8.76 (1H, t, J=5.7 Hz), 9.13 (2H, br): HPLC-MS (ESI):     Calcd for C₂₂H₂₈N₄O₅S [M+H]⁺ 461, Found: 461. -   Molecular weight: 497.017 -   Activity grade Ca²⁺: A

Example 22-3

-   (1) To a solution of tert-butyl     4-{[5-{[(2-cyanoethyl)amino]carbonyl}-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-1-piperazinecarboxylate     (0.396 g, 0.730 mmol) in CH₃CN (3.0 ml) was added triphenylphosphine     (0.230 g, 0.876 g). The mixture was gently heated with a heat gun     until a clear solution resulted. The mixture was cooled with an     ice-water bath, and diethyl azodicarboxylate (0.138 ml, 0.876 mmol)     and azidotrimethylsilane (0.116 ml, 0.876 mmol) were added     successively. The mixture was allowed to warn to room temperature,     and the stirring was continued overnight. A solution of     triphenylphosphine (0.115 g, 0.438 mmol), diethyl azodicarboxylate     (0.069 ml, 0.438 mmol) and azidotrimethylsilane (0.058 ml, 0.437     mmol) were added successively, and the mixture was stirred for 3     days. The mixture was diluted with EtOAc, and washed with water. The     separated organic phase was washed with saturated NaHCO₃ solution,     water and brine, dried over Na₂SO₄. The solvent was evaporated in     vacuo. The residue was purified by column chromatography on silica     gel (Hexane/EtOAc=1/1) to give tert-butyl     4-{[5-[1-(2-cyanoethyl)-1H-tetraazol-5-yl]-2-(3,5-dimethylphenoxy)phenyl]sulfonyl)-1-piperazinecarboxylate     (0.338 g, 81.6%).

-   (2) To a solution of tert-butyl     4-([5-[1-(2-cyanoethyl)-1H-tetraazol-5-yl]-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-1-piperazinecarboxylate     (0.030 g, 0.053 mmol) in 1,4-dioxane (1.0 ml) was added 4N HCl in     1,4-dioxane (3.0 ml). The mixture was stirred at room temperature     for 2 hrs, then concentrated in vacuo. The residue was     recrystallized from Et₂O, washed with Et₂O and dried in vacuo to     give     3-{5-[4-(3,5-dimethylphenoxy)-3-(1-piperazinylsulfonyl)phenyl]-1H-tetraazol-1-yl}propanenitrile     hydrochloride (0.021 g, 78.8%): mp 125° C. ¹H NMR (500 MHz, DMSO-d₆)     δ 2.32 (6H, s), 3.18 (4H, br), 3.23 (2H, t, J=6.3 Hz), 3.50 (4H,     br), 4.76 (2H, t, J=6.3 Hz), 6.89 (2H, s), 6.99 (1H, s), 7.10 (1H,     d, J=8.5 Hz), 8.04 (1H, dd, J=1.9, 8.5 Hz), 8.26 (1H, d, J=1.9 Hz),     9.05 (2H, br); HPLC-MS (ESI): Calcd for C₂₂H₂₅N₇O₃S [M+H]⁺ 468,     Found: 468. -   Molecular weight: 504.014 -   Activity grade Ca²⁺: A

Example 22-4

-   (1) To a solution of tert-butyl     4-{[5-[1-(2-cyanoethyl)-1H-tetraazol-5-yl]-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-1-piperazinecarboxylate     (0.150 g, 0.264 mmol) in CH₂Cl₂ (2.0 ml) was added DBU (0.119 ml,     0.793 mmol), and the mixture was stirred at room temperature for 2.5     hrs. The mixture was diluted with EtOAc, and washed with 1N HCl. The     separated organic phase was washed with water and brine, dried over     Na₂SO₄. The solvent was evaporated in vacuo. The residue was     recrystallized from Et₂O. The solid was collected by filtration,     washed with Et₂O and dried in vacuo to give tert-butyl     4-{[2-(3,5-dimethylphenoxy)-5-(1H-tetraazol-5-yl)phenyl]sulfonyl}-1-piperazinecarboxylate     (0.096 g, 70.6%).

-   (2) To a solution of tert-butyl     4-{[2-(3,5-dimethylphenoxy)-5-(1H-tetraazol-5-yl)phenyl]sulfonyl}-1-piperazinecarboxylate     (0.050 g, 0.097 mmol) in 1,4-dioxane (1.0 ml) was added 4N HCl in     1,4-dioxane (3.0 ml). The mixture was stirred at room temperature     for 2 hrs. The precipitate was collected by filtration, washed with     1,4-dioxane and Et₂O, dried in vacuo to give     1-{[2-(3,5-dimethylphenoxy)-5-(1H-tetraazol-5-yl)phenyl]sulfonyl)piperazine     hydrochloride (0.037 g, 84.4%):mp 213° C. ¹H NMR (500 MHz, DMSO-d₆)     δ 2.31 (6H, s), 3.18 (4H, br), 3.48 (4H, br), 6.86 (2H, s), 6.96     (1H, s), 7.14 (1H, d, J=8.8 Hz), 8.29 (1H, dd, J=2.2, 8.8 Hz), 8.56     (1H, d, J=2.2 Hz), 9.07 (2H, br); HPLC-MS (ESI): Calcd for     C₁₉H₂₂N₆O₃S [M+H]⁺ 415, Found: 415. -   Molecular weight: 450.950 -   Activity grade Ca²⁺:A

Example 23-1

-   (1) 2-(3,5-dimethylphenoxy)-4-nitrobenzic acid was prepared by the     same procedure of 4-(3,5-dichlorophenoxy)-3-nitrobenzoic acid     (Example 13-(1)).

-   (2) The mixture of 2-(3,5-dimethylphenoxy)-4-nitrobenzic acid (1.72     g, 6.00 mmol), diphenyl phosphoroazidate (1.98 g, 7.20 mmol) and     triethylamine (1.00 ml, 7.20 mmol) in tert-butanol was heated to     80° C. overnight. After cooled to room temperature, the reaction     mixture was poured into water and the resulting mixture was     extracted with EtOAc. The extract was washed with brine, and dried     over MgSO₄. The solvent was evaporated in vacuo. The residue was     purified by chromatography on silica gel (CHCl₃/Hexane=65/35) to     give a colorless oil. The obtained oil was dissolve into 4N HCl in     1,4-dioxane and the resulting mixture was stirred overnight. Then     the reaction mixture was condensed under reduced pressure. The     obtained material was dissolved in THF followed addition of ether.     The precipitate was collected by filtration, washed with ether and     dried in vacuo to give 2-(3,5-dimethylphenoxy)-4-nitroaniline     hydrochloride as yellow powder. (0.18 g, 10%)

-   (3) 2-(3,5-dimethylphenoxy)-4-nitrobenzensulfonylchloride was     prepared by the same procedure of     5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonylchloride (Example     13-(5)).

-   (4) tert-Butyl     4-(2-(3,5-dimethylphenoxy)-4-nitrophenylsulfonyl}-1-piperazinecarboxylate     was prepared by the same procedure of     1-{5-cyano-2-(3,5-dichlorophenoxy)phenylsulfony}-(3S)-(tert-butoxycarbonylamino)pyrrolidine     (Example 13-1(6)).

-   (5) 1-{2-(3,5-dimethylphenoxy)-4-nitrophenylsulfonyl}piperazine     hydrochloride was prepared by the same procedure of     1-{5-cyano-2-(3,5-dichlorophenoxy)phenylsulfonyl}-(3S)-aminopyrrolidine     hydrochloride (Example 13-(7)):mp 284° C.

¹H NMR (500 MHz, DMSO-d₆) □; 2.32 (6H, s), 3.18-3.19 (4H, m), 3.51-3.53 (4H, m), 6.92 (2H, s), 7.01 (1H, s), 7.52 (1H, d, J=1.9 Hz), 8.08 (1H, dd, J 8.5, 2.2 Hz), 8.15 (1H, d, J=8.5 Hz), 9.28 (2H, br); HPLC-MS (ESI): calcd for C₁₈H₂₂ClFN₂O₃S [M+H]⁺ 392, Found: 392.

-   Molecular weight: 427.910 -   Activity grade Ca²⁺:A

Example 24-1

-   (1) To a vigorously stirred mixture of m-nitrobenzenesulfonyl     chloride (3.00 g, 13.5 mmol), trifluoroacetic acid (6.5 ml, 84.4     mmol) and conc. sulfuric acid (2.6 ml, 47.8 mmol) was added     N-bromosuccinimide (3.61 g, 20.3 mmol) in portions over an hour     period. This mixture was stirred at 45° C. for 88 hrs. The mixture     was poured into 25 ml of ice-water, the organic layer was separated,     and the aqueous layer was extracted with CH₂Cl₂ to remove very small     amount of 3-bromo-5-nitrobenzenesulfonyl chloride. The aqueous layer     was concentrated to give a mixture of 3-bromo-5-nitrobenzenesulfonic     acid, 3-nitrobenzenesulfonic acid and sulfuric acid. To the mixture     was added 8N NaOH and the resulting precipitate was collected by     filtration and washed with water to give sodium     3-bromo-5-nitrobenzenesulfonate (256 mg, 6.2%).

-   (2) A suspension of sodium 3-bromo-5-nitrobenzenesulfonate (140 mg,     0.46 mmol) in phosphorus oxychloride (1.0 ml, 10.7 mmol) was     refluxed for 1 hr. Phosphorus pentachloride (192 mg, 0.92 mmol) was     added and the mixture was stirred at 150° C. for additional 1 hr.     After cooling to room temperature, the mixture was evaporated. The     resulting residue was neutralized with 4N NaOH and the product was     extracted with EtOAc. The organic layer was dried over anhydrous     MgSO₄. The solvent was evaporated in vacuo to give     3-bromo-5-nitrobenzenesulfonyl chloride (103 mg, 74%).

-   (3) To a mixture of 3-bromo-5-nitrobenzenesulfonyl chloride (100 mg,     0.33 mmol) and N,N-diisopropylethylamine (0.069 ml, 0.40 mmol) in     THF (3 ml) was added dropwise the solution of tert-butyl     1-piperazinecarboxylate (68 mg, 0.37 mmol) in THF (2 ml) at 0° C.     The mixture was stirred at room temperature for 1 hr. Solvent was     removed by evaporation. The resulting residue was diluted with     CH₂Cl₂ and washed with 0.5 N HCl, brine, aqueous NaHCO₃, and brine,     then dried over anhydrous MgSO₄. The solvent was removed by     evaporation and the residue was purified by preparative TLC on     silica gel (Hexane/EtOAc=2/1) to give tert-butyl     4-[(3-bromo-5-nitrophenyl)sulfonyl]-1-piperazinecarboxylate (116 mg,     77%); MS (FAB): Calcd for C₁₅H₂₀BrN₃O₆S [M+H]⁺ 450 and 452, Found:     350 and 352 (−Boc).

-   (4) To a suspension of sodium hydride (6.7 mg, 0.17 mmol) in DMF     (2 ml) was added 3,5-dimethylphenol (20 mg, 0.17 mmol) at 0° C. This     mixture was stirred for 10 min. tert-butyl     4-[(3-bromo-5-nitrophenyl)sulfonyl]-1-piperazinecarboxylate (50 mg,     0.11 mmol) was added to and the mixture was stirred at 90° C. for     2.5 hrs. The reaction mixture was diluted with EtOAc and washed with     aqueous NaHCO₃ and brine. The organic layer was dried over anhydrous     MgSO₄. The solvent was evaporated in vacuo. The residue was purified     by preparative TLC on silica gel (Hexane/EtoAc=2/1). The resulting     solid was suspended in ether/hexane/CHCl₃ and collected by     filtration to give tert-butyl     4-{[3-bromo-5-(3,5-dimethylphenoxy)phenyl]sulfonyl}-1-piperazinecarboxylate     (19.5 mg, 33%): mp 155° C.; HPLC-MS (ESI): Calcd for C₂₃H₂₉BrN₂O₅S     [M+H]⁺ 525 and 527, Found: 425 and 427 (−Boc).

-   (5) A solution of tert-butyl     4-{[3-bromo-5-(3,5-dimethylphenoxy)phenyl]-sulfonyl}-1-piperazinecarboxylate     (17 mg, 0.032 mmol) in 4N HCl solution in 1,4-dioxane (2 ml, 8 mmol)     was stirred at room temperature overnight. Solvent was removed by     evaporation to give     1-{[3-bromo-5-(3,5-dimethylphenoxy)phenyl]sulfonyl}piperazine     hydrochloride (14.9 mg, 99%): mp >84° C. (decomposed); ¹H NMR (500     MHz, DMSO-d₆) δ 2.30 (6H, s), 3.20 (8H, br), 6.79 (2H, s), 6.93 (1H,     S), 7.25 (1H, s), 7.60 (1H, d, J=2.0 Hz), 7.66 (1H, s), 8.99 (1H,     br); HPLC-MS (ESI): Calcd for C₁₈H₂₁BrN₂O₃S [M+H]+425 and 427,     Found: 425 and 427. -   Molecular weight: 461.808 -   Activity grade Ca²⁺:A

Example 25-1

-   (1) To a mixture of 4-hydroxypyridine-3-sulfonic acid (1.00 g, 5.71     mmol) and phosphorus pentachloride (2.38 g, 11.4 mmol) was added     phosphorus oxychloride (1.06 ml, 11.4 mmol) dropwise at 0° C. The     mixture was refluxed for 5 hrs. After the mixture was cooled to room     temperature, cooled aqueous NaHCO₃ was added to the mixture     carefully. The mixture was extracted with CHCl₃. The organic layer     was dried over anhydrous MgSO₄. The solvent was evaporated in vacuo     to give 4-chloro-3-pyridinesulfonyl chloride as colorless oil (0.97     g, 80.1%).

-   (2) A mixture of 4-chloro-3-pyridinesulfonyl chloride (0.97 g, 4.57     mmol), tert-butyl 1-piperazinecarboxylate (0.94 g, 5.03 mmol), and     N,N-diisopropylethylamine (0.88 ml, 5.03 mmol) in THF (50 ml) was     stirred at room temperature overnight. The mixture was concentrated     in vacuo. The residue was washed with ice water, then was dried in     vacuo to give tert-butyl     4-[(4-chloro-3-pyridinyl)sulfonyl]-1-piperazinecarboxylate as a pale     yellow solid (1.51 g, 91.3%).

-   (3) To a solution of 3,5-dimethylphenol (37.1 mg, 0.30 mmol) in     1,4-dioxane (1 ml) was added sodium hydride (60% oil suspension,     13.3 mg, 0.33 mmol) portionwise. The mixture was stirred at room     temperature for 30 min. To the mixture was added a solution of     tert-butyl     4-[(4-chloro-3-pyridinyl)sulfonyl]-1-piperazinecarboxylate (100 mg,     0.28 mmol) in 1,4-dioxane (1 ml) slowly. The mixture was stirred at     70° C. overnight. After the mixture was cooled to room temperature,     the mixture was concentrated in vacuo. The residue was washed with     ice water, dried in vacuo to give tert-butyl     4-{[4-(3,5-dimethylphenoxy)-3-pyridinyl]sulfonyl}-1-piperazinecarboxylate     (110 mg, 88.9%) as a white solid.

-   (4) To a solution of tert-butyl     4-{[4-(3,5-dimethylphenoxy)-3-pyridinyl]sulfonyl}-1-piperazinecarboxylate     (23.4 mg, 0.0523 mmol) in CH₂Cl₂ (1 ml) was added 4N HCl in     1,4-dioxane (0.25 ml). The mixture was stirred at room temperature     overnight. The mixture was concentrated in vacuo. The residue was     triturated with diethylether, dried in vacuo to give     1-{[4-(3,5-dimethylphenoxy)-3-pyridinyl]sulfonyl}piperazine     hydrochloride (17 mg, 76%) as a white solid: mp 220° C.; 1H NMR (300     MHz, DMSO-d₆) δ 2.33 (6H, s), 3.19 (4H, m), 3.52 (4H, m), 6.84 (1H,     d, J=6 Hz), 7.00 (2H, s), 7.03 (1H, s), 8.65 (1H, d, J=6 Hz), 8.88     (1H, s), 9.35 (2H, br); HPLC-MS (ESI): Calcd for C₁₇H₂₁N₃O₃S [M+H]⁺     348, Found: 348. -   Molecular weight: 420.361 -   Activity grade RBA: B

Activity grade Ca²⁺: A

In the similar manner as described in Example 25-1 above, compounds in Example 25-2 as shown in Table 25 were synthesized.

TABLE 25 EX. No. moistructure MW M + 1 mp RBA Ca2+ 25-2

461.19704 388 213-215 A A

Example 26-1

-   (1) To a suspension of sodium hydride (4.5 mg, 0.11 mmol) in THF     (2 ml) was added     2-[(3,5-dichlorophenyl)sulfanyl]-5-nitro-N-[2-(1-piperidinyl)ethyl]benzenesulfonamide     (50 mg, 0.10 mmol) at 0° C. The mixture was stirred at 0° C. for 10     min. Methyl iodide (0.01 ml, 0.15 mmol) was added and the mixture     was stirred at 0° C. for 30 min then room temperature overnight. The     reaction mixture was diluted with EtOAc and washed with aqueous     NaHCO₃ and brine. The organic layer was dried over anhydrous MgSO₄.     The solvent was evaporated in vacuo. The residue was purified by     preparative TLC on silica gel (CHCl₃/MeOH=9/1) to give     2-[(3,5-dichlorophenyl)sulfanyl]-N-methyl-5-nitro-N-[2-(1-piperidinyl)ethyl]benzenesulfonamide     (18 mg, 35.0%): mp 113-114° C.; ¹H NMR (300 MHz, CDCl3) δ 1.42 (2H,     m), 1.52 (4H, m), 2.41 (4H, m), 2.57 (2H, t, J=7.0 Hz), 3.03 (3H,     s), 3.47 (2H, t, J=7.0 Hz), 7.07 (1H, d, J=8.7 Hz), 7.45 (2H, m),     7.51 (1H, t, J=1.9 Hz), 8.14 (1H, dd, J=2.3, 8.7 Hz), 8.79 (1H, d,     J=2.3 Hz); HPLC-MS (ESI): Calcd for C₂₀H₂₃Cl₂N₃O₄S₂ [M+H]⁺ 504 and     506, Found: 504 and 506. -   Molecular weight: 504.458 -   Activity grade RBA: A

Activity grade Ca²⁺: A

In the similar manner as described in Example 26-1 above, compounds in Example 26-2 and 26-3 as shown in Table 26 were synthesized.

TABLE 26 EX. No. moistructure MW M + 1 mp RBA Ca2+ 26-2

490.40935 490 108-110 A 26-3

506.47395 506 144-145 A

Operative Examples Relating to Pharmaceutical Compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet

Composition

100 mg of the compound of Example 1-1, 50 mg of lactose (monohydrate), 50 mg of maize starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of magnesium stearate.

Tablet weight 212 mg, diameter 8 mm, curvature radius 12 mm.

Preparation

The mixture of active component, lactose and starch is granulated with a 5% solution (m/m) of the PVP in water. After drying, the granules are mixed with magnesium stearate for 5 min. This mixture is moulded using a customary tablet press (tablet format, see above). The moulding force applied is typically 15 kN.

Orally Administrable Suspension

Composition

1000 mg of the compound of Example 1-1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pa., USA) and 99 g of water.

A single dose of 100 mg of the compound according to the invention is provided by 10 ml of oral suspension.

Preparation

The Rhodigel is suspended in ethanol and the active component is added to the suspension. The water is added with stirring. Stirring is continued for about 6 h until the swelling of the Rhodigel is complete. 

1. A sulfonamide derivative of the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof:

X represents phenyl, which is substituted by 0 to 5 substituents independently selected from the group consisting of R¹, R², R³, R⁴ and R⁰, or pyridine, which is substituted by 0 to 5 substituents independently selected from the group consisting of R¹, R², R³ and R⁴ wherein R¹ is hydrogen, halogen, hydroxy, straight- or branched-C₁₋₆ alkyl optionally mono-, di-, or tri-substituted by halogen, or by straight- or branched-C₁₋₆ alkoxy, straight- or branched-C₁₋₆ alkoxy carbonyl, amino, straight- or branched-C₁₋₆ alkylamino, di(straight- or branched-C₁₋₆ alkyl)amino, straight- or branched-C₁₋₆ alkanoyl, nitro, or phenyl, R² is hydrogen, halogen, straight- or branched-C₁₋₆ alkyl optionally mono-, di-, or tri- substituted by halogen, or by straight- or branched-C₁₋₆ alkoxy, or cyano, or R¹ and R² together form benzene ring or C₅₋₈ cycloalkyl fused to the adjacent phenyl, R³ is hydrogen, halogen, or straight- or branched-C₁₋₆ alkyl, R⁴ is hydrogen, halogen, or straight- or branched-C₁₋₆ alkyl, R⁰ is hydrogen, halogen, or straight- or branched-C₁₋₆ alkyl, Y represents O, NH, NCH₃S, S(O), or SO₂; Z¹ represents CH; Z² represents CH; R⁵ is chloro, iodo, nitro, or cyano; R⁶ is hydrogen; R⁷ represents

wherein n represents an integer selected from 1 to 3, m represents an integer selected from 0 to 3, R⁷¹ is hydrogen, C₃₋₈ cycloalkyl optionally interrupted by NH, N—CH₃ or O, straight- or branched C₁₋₆ alkoxycarbonyl, phenyl optionally substituted by straight- or branched C₁₋₆ alkyl, benzyl, formyl, or straight- or branched C₁₋₆ alkyl wherein the alkyl is optionally substituted by hydroxy, straight- or branched-C₁₋₆ alkoxy, hydroxy straight- or branched-C₁₋₆ alkoxy, carboxy, straight- or branched-C₁₋₆ alkoxycarbonyl, straight- or branched-C₁₋₆ alkylthio, di(straight- or branched-C₁₋₆ alkyl)amino, from 1 to 3 halogens, or C₃₋₈ cycloalkyl optionally interrupted by NH or O, R⁷¹¹ and R⁷¹² are independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, straight- or branched-C₁₋₆ alkyl optionally substituted by hydroxy, carboxy, from 1 to 3 halogens, carbamoyl, di(straight-or branched C₁₋₆ alkyl)amino carbonyl, and —NR^(711a)R^(711b), wherein R^(711a) and R^(711b) are independently selected from the group consisting of hydrogen, straight- or branched-C₁₋₆ alkyl, straight- or branched-C₁₋₆ alkanoyl, and straight- or branched-C₁₋₆ alkylsulfonyl, or R⁷¹ and R⁷¹¹ may form, together with the N atom adjacent to R⁷¹, a 5 to 8 membered saturated ring.
 2. The sulfonamide derivative of the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1, wherein R¹ is halogen, or straight- or branched-C₁₋₆ alkyl optionally mono-, di-, or tri-substituted by halogen; R² is halogen, or straight- or branched-C₁₋₆ alkyl optionally mono-, di-, or tri-substituted by halogen; R³ is hydrogen; R⁴ is hydrogen; R⁰ is hydrogen; Y is O, NH, NCH₃, S, S(O), or SO₂; R⁵ is halogen, nitro, or cyano; R⁶ hydrogen; and R⁷ represents

wherein n represents an integer selected from 1 to 3, m represents an integer selected from 0 to 3, R⁷¹ is hydrogen, straight- or branched-C₁₋₆ alkyl optionally substituted by hydroxy or hydroxy straight- or branched-C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, straight- or branched-C₁₋₆ alkoxycarbonyl, phenyl optionally substituted by straight- or branched-C₁₋₆ alkyl, benzyl, or formyl, R⁷¹¹ and R⁷¹² are independently selected from the group consisting of hydrogen, halogen, carboxy, and straight- or branched C₁₋₆ alkyl, or R⁷¹ and R⁷¹¹ may form, together with the N atom adjacent to R⁷¹, a 5 to 8 membered saturated ring.
 3. The sulfonamide derivative of the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1, wherein R¹ and R² are identical or different and represent chloro, or methyl; R³ is hydrogen or fluoro; R⁴ is hydrogen; R⁰ is hydrogen; Y is O, NH, NCH₃, S, S(O), or SO₂; R⁵ is chloro, iodo, nitro, or cyano; R⁶ is hydrogen; and R⁷ represents

wherein n represents an integer selected from 1 to 3, m represents an integer selected from 0 to 3, R⁷¹ is hydrogen, straight- or branched-C₁₋₆ alkyl optionally substituted by hydroxy or hydroxy straight- or branched-C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, straight- or branched-C₁₋₆ alkoxycarbonyl, phenyl optionally substituted by straight- or branched-C₁₋₆ alkyl, benzyl, or formyl, R⁷¹¹ and R⁷¹² are independently selected from the group consisting of hydrogen, halogen, carboxy, and straight-or branched-C₁₋₆ alkyl, or R⁷¹ and R⁷¹¹ may form, together with the N atom adjacent to R⁷¹, a 5 to 8 membered saturated ring.
 4. The sulfonamide derivative of the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1, wherein R¹ is hydrogen, fluoro, chloro, bromo, methyl, isopropyl, butyl, tert-butyl, trifluoromethyl, methoxy, amino, dimethylamino, acetyl, or nitro; R² is hydrogen, fluoro, chloro, methyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, or cyano; R³ is hydrogen or fluoro; R⁴ is hydrogen; R⁰ is hydrogen; Y is O, NH, NCH₃, S, S(O), or SO₂; R⁵ is chloro, iodo, nitro, or cyano; R⁶ is hydrogen; and R⁷ represents

wherein n represents an integer 1, m represents an integer selected from 1 or 2, R⁷¹ represents hydrogen, methyl, ethyl or isopropyl; R⁷¹¹ represents hydrogen, methyl, or carboxy; R⁷¹² represents hydrogen or methyl, or R⁷¹ and R⁷¹¹ may form, together with the N atom adjacent to R⁷¹, a 5 membered saturated ring.
 5. The sulfonamide derivative of the formula (I-2), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof;

wherein R¹ is hydrogen, halogen, straight- or branched-C₁₋₆ alkyl optionally mono-, di-, or tri-substituted by halogen, straight- or branched-C₁₋₆ alkoxy, straight- or branched-C₁₋₆ alkoxy carbonyl, amino, straight- or branched -C₁₋₆ alkylamino, di(straight- or branched-C₁₋₆ alkyl)amino, straight- or branched-C₁₋₆ alkanoyl, or nitro, R² is hydrogen, halogen, straight- or branched-C₁₋₆ alkyl optionally mono-, di-, or tri-substituted by halogen, straight- or branched-C₁₋₆ alkoxy, or cyano, or R¹ and R² may form benzene ring or C₅₋₈ cycloalkyl fused to the adjacent phenyl; R³ is hydrogen or halogen, Y represents O, NH, NCH₃, S, S(O), or SO₂; R⁵ is chloro, iodo, nitro, or cyano; R⁶ is hydrogen; R⁷ represents

wherein n represents an integer selected from 1 to 3, m represents an integer selected from 0 to 3, R⁷¹ is hydrogen, straight- or branched-C₁₋₆ alkyl optionally substituted by hydroxy or hydroxy straight- or branched-C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, straight- or branched-C₁₋₆ alkoxycarbonyl, phenyl optionally substituted by straight- or branched-C₁₋₆ alkyl, benzyl, or formyl, R⁷¹¹ and R⁷¹² are independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, cyano, straight- or branched C₁₋₆ alkyl optionally substituted by hydroxy, carboxy, or 1 to 3 halogens, carbamoyl, di (straight- or branched C₁₋₆ alkyl) amino carbonyl, or —NR^(711a)R^(711b) wherein R^(711a) and R^(711b) are independently selected from the group consisting of hydrogen, straight- or branched-C₁₋₆ alkyl, straight- or branched-C₁₋₆ alkanoyl, or straight- or branched-C₁₋₆ alkylsulfonyl, or R⁷¹ and R⁷¹¹ may form, together with the N atom adjacent to R⁷¹, a 5 to 8 membered saturated ring.
 6. The sulfonamide derivative of the formula (I-2), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 5, wherein R¹ is hydrogen, halogen, or straight- or branched-C₁₋₆ alkyl optionally mono-, di-, or tri-substituted by halogen; R² is hydrogen, halogen, or straight- or branched-C₁₋₆ alkyl optionally mono-, di-, or tri-substituted by halogen; R³ is hydrogen or halogen, Y is O, NH, NCH₃, S, S(O), or SO₂; R⁵ is halogen, nitro, or cyano; R⁶ is hydrogen; and R⁷ represents

wherein n represents an integer selected from 1 to 3, m represents an integer selected from 0 to 3, R⁷¹ is hydrogen, straight- or branched-C₁₋₆ alkyl optionally substituted by hydroxy or hydroxy straight- or branched-C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, straight- or branched-C₁₋₆ alkoxycarbonyl, phenyl optionally substituted by straight- or branched-C₁₋₆ alkyl, benzyl, or formyl, R⁷¹¹ represents hydrogen, methyl, or carboxy, R⁷¹² represents hydrogen or methyl, or R⁷¹ and R⁷¹¹ may form, together with the N atom adjacent to R⁷¹, a 5 to 8 membered saturated ring.
 7. The sulfonamide derivative of the formula (I-2), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 5, wherein R¹, R² and R³ are independently selected from the group consisting of hydrogen, chloro, and methyl; Y is O, NH, NCH₃, S, S(O), or SO₂; R⁵ is chloro, iodo, nitro, or cyano; R⁶ is hydrogen; and R⁷ represents

wherein n represents an integer selected from 1 to 3, m represents an integer selected from 1 to 3, R⁷¹ is hydrogen, straight- or branched-C₁₋₆ alkyl optionally substituted by hydroxy or hydroxy straight- or branched-C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, straight- or branched-C₁₋₆ alkoxycarbonyl, phenyl optionally substituted by straight- or branched-C₁₋₆ alkyl, benzyl, or formyl, R⁷¹¹ represents hydrogen, methyl, or carboxy or R⁷¹ and R⁷¹¹ may form, together with the N atom adjacent to R⁷¹, a 5 to 8 membered saturated ring. R¹ is hydrogen, fluoro, chloro, bromo, methyl, isopropyl, butyl, tert-butyl, trifluoromethyl, methoxy, amino, dimethylamino, acetyl, or nitro; R² is hydrogen, fluoro, chloro, methyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, or cyano; R³ is hydrogen or fluoro; Y is O, NH, NCH₃, S, S(O), or SO₂; R⁵ is hydrogen, fluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, methoxy, amino, acetylamino, isobutylcarbonylamino, tert-butylcarbonylamino, benzoylamino, benzylcarbonylamino, phenethylcarbonylamino, methylbenzoylamino, naphthylcarbonylamino, thenoylamino, nitro, cyano, methylsulfonyl, dimethyaminosulfonyl, piperazinosulfonyl, dimethyaminocarbonyl, or piperazinocarbonyl; R⁶ is hydrogen, methyl, or methoxy; or R⁵ and R⁶ may form a pyrrole ring fused to adjacent phenyl, and R⁷ represents


8. The sulfonamide derivative of formula (I-2), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 5, wherein R¹ is chloro, bromo, or methyl; R² is hydrogen, chloro, bromo, or methyl; R³ is hydrogen or fluoro; Y represents O, S, or S(O); R⁵ represents hydrogen, chloro, nitro, or cyano; R⁶ represents hydrogen; R⁷ represents

wherein R⁷¹ represents hydrogen, methyl, ethyl or isopropyl; R⁷¹¹ represents hydrogen, methyl or carboxy; and R⁷¹² represents hydrogen or methyl.
 9. The sulfonamide derivative, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1, wherein said sulfonamide derivative is selected from the group consisting of: 1-{[2-(3,5-dimethylphenoxy)-5-nitrophenyl]sulfonyl}-4-ethylpiperazine, 1-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}piperazine, 1-{[2-( 3,5-dimethylphenoxy)-5-nitrophenyl]sulfonyl}-4-isopropylpiperazine, 4-(3,5-dimethylphenoxy)-3-(1-piperazinylsulfonyl)benzonitrile, 1-{[5-chloro-2-(3,5-dimethylphenoxy)phenyl]sulfonyl}-4-ethylpiperazine, 1-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-4-( 1-pyrrolidinyl)piperidine, 4-(3,5-dichlorophenoxy)-3-(1-piperazinylsulfonyl)benzonitrile, 4-[(3,5-dichlorophenyl)sulfanyl]-3-(1-piperazinylsulfonyl)benzonitrile, 4-[(3,5-dichlorophenyl)sulfinyl]-3-(1-piperazinylsulfonyl)benzonitrile, 1-{[2-(3,5-dibromophenoxy)-5-nitrophenyl]sulfonyl}piperazine, 1-{[2-(3,5-dichloro-2-fluorophenoxy)-5-nitrophenyl]sulfonyl}piperazine, 1-{[5-cyano-2-(3,5-dichlorophenoxy)phenyl]sulfonyl}-2-piperazinecarboxylic acid, 1-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-2-piperazinecarboxylic acid, 1-{[2-(3,5-dimethylphenoxy)-5-nitrophenyl]sulfonyl}-1,4-diazepane, 1-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-1,4-diazepane, 1-{[2-(3,5-dichlorophenoxy)-5-nitrophenyl]sulfonyl}-3,5-dimethylpiperazine, 3-(1,4-diazepan-1-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzonitrile, and 3-(1,4-diazepan-1-ylsulfonyl)-4-[(3,5-dichlorophenyl)sulfanyl]benzonitrile.
 10. A compound of formula (I-2), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 5, wherein R¹ is hydrogen, fluoro, chloro, bromo, methyl, isopropyl, butyl, tert-butyl, trifluoromethyl, methoxy, amino, dimethylamino, acetyl, or nitro; R² is hydrogen, fluoro, chloro, methyl, isopropyl, tert-butyl, trifluoromethyl, methoxy, or cyano; or R³ is hydrogen or flouro; Y is O, NH, NCH₃, S, S(O), or SO₂; R⁵ is hydrogen, fluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, methoxy, amino, acetylamino, isobutylcarbonylamino, tert-butylcarbonylamino, benzoylamino, benzylcarbonylamino, phenethylcarbonylamino, methylbenzoylamino, napthylcarbonylamino, thenoylamino, nitro, cyano, methylsulfonyl, dimethylaminosulfonyl, piperazinosulfonyl, dimethylaminocarbonyl, or piperinocarbonyl; R⁶ is hydrogen, methyl, or methoxy; or R⁵ and R⁶ may form a pyrrole ring fused to adjacent phenyl; and R⁷ represents

wherein n represents an integer 1; m represents an integer 1 or 2; R⁷¹ is hydrogen, methyl, ethyl, isopropyl, sec-butyl, branched pentyl, hydroxyethyl, hydroxyethoxyethyl, cyclopentyl, cyclohexyl, tert-butoxyethyl, phenyl, tolyl, benzyl, or formyl; R⁷¹¹ is hydrogen methyl, or carboxy; R⁷¹² is hydrogen or methyl; or R⁷¹ and R⁷¹¹ may form, together with the N atom adjacent to -R⁷¹, a 5 membered saturated ring.
 11. A compound of claim 1, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof, wherein the compound is selected from the group consisting of: 1-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3,5-difluorophenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3,5-dimethoxyphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3,5-bis(trifluoromethyl)phenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3,5-di-tert-butylphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3-isopropyl-5-methylphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3-isopropyl-5-methylphenoxy)-5-nitrophenylsulfonyl)piperazine, 3-(4-nitro-2-(piperazin-1-ylsulfonyl)phenoxy)benzonitrile, 1-(2-(naphthalen-1-yloxy)-5-nitrophenylsulfonyl)piperazine, 1-(5-nitro-2-(o-tolyloxy)phenylsulfonyl)piperazine, 4-(4-nitro-2-(piperazin-1-ylsulfonyl)phenoxy)aniline, 1-(2-(2-fluorophenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3-fluorophenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(5-nitro-2-(p-tolyloxy)phenylsulfonyl)piperazine, 1-(5-nitro-2-(m-tolyloxy)phenylsulfonyl)piperazine, 1-(5-nitro-2-phenoxyphenylsulfonyl)piperazine, 1-(2-(4-methoxyphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(4-fluorophenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(4-tert-butylphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(4-chlorophenoxy)-5-nitrophenylsulfonyl)piperazine, 4-(4-nitro-2-(piperazin-1-ylsulfonyl)phenoxy)benzonitrile, 1-(5-nitro-2-(m-tolyloxy)phenylsulfonyl)piperazine, 1-(2-(3-fluorophenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(2-methoxyphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(2-chlorophenoxy)-5-nitrophenylsulfonyl)piperazine, 2-(4-nitro-2-(piperazin-1-ylsulfonyl)phenoxy)benzonitrile, 1-(2-(4-nitro-2-(piperazin-1-ylsulfonyl)phenoxy)phenyl)ethanone, 1-(3-(4-nitro-2-(piperazin-1-ylsulfonyl)phenoxy)phenyl)ethanone, N,N-dimethyl-3-(4-nitro-2-(piperazin-1-ylsulfonyl)phenoxy)aniline, 1-(2-(3,5-dichlorophenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(5-nitro-2-(3-(trifluoromethyl)phenoxy)phenylsulfonyl)piperazine, 1-(2-(3-tert-butylphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3-methoxy-5-methylphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(5-nitro-2-(3-nitrophenoxy)phenylsulfonyl)piperazine, 1-(2-(3-bromophenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(2-butylphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3,5-dichlorophenoxy)-5-fluorophenylsulfonyl)piperazine, 1-(2-(3,5-dimethylphenoxy)-4-methylphenylsulfonyl)piperazine, methyl 5-(4-nitro-2-(piperazin-1-ylsulfonyl)phenoxy)nicotinate, 1-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)-2,5-dimethylpiperazine, 1-(2-(5-chloropyridin-3-yloxy)-5-nitrophenylsulfonyl)piperazine, 1-(5-chloro-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperazine, 1-(5-bromo-2-(3,5-dichlorophenoxy)phenylsulfonyl)piperazine, 1-(2-(3,5-dimethylphenoxy)-6-fluorophenylsulfonyl)piperazine, 1-(2-(4-chloro-3-methylphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(5-nitro-2-(2,3,6-trimethylphenoxy)phenylsulfonyl)piperazine, 1-(2-(2,3-dimethylphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3,4-dimethylphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(2,5-dimethylphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(5-nitro-2-(2,3,5-trimethylphenoxy)phenylsulfonyl)piperazine, 1-(2-(2-isopropyl-5-methylphenoxy)-5-nitrophenylsulfonyl)piperazine, 3-(4-nitro-2-(piperazin-1-ylsulfonyl)phenoxy)aniline, 1-(2-(biphenyl-3-yloxy)-5-nitrophenylsulfonyl)piperazine, 1-(5-nitro-2-(3,4,5-trimethylphenoxy)phenylsulfonyl)piperazine, 1-(2-(6-methylpyridin-3-yloxy)-5-nitrophenylsulfonyl)piperazine, 3-methyl-5-(4-nitro-2-(piperazin-1-ylsulfonyl)phenoxy)phenol hydrochloride, 1-(5-nitro-2-(5,6,7,8-tetrahydronaphthalen-2-yloxy)phenylsulfonyl)piperazine, 1-(5-nitro-2-(2,3,4,5,6-pentafluorophenoxy)phenylsulfonyl)piperazine, 1-(5-nitro-2-(2,3,5,6-tetrafluorophenoxy)phenylsulfonyl)piperazine, 1-(2-(5-methyl-2-nitrophenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(4-chloro-3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(2-chloro-5-methylphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(4-chloro-2-isopropyl-5-methylphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(2,3-dichlorophenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(2,5-dichlorophenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3-chloro-4-fluorophenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(5-nitro-2-(2,3,5-trichlorophenoxy)phenylsulfonyl)piperazine, 2-(4-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)piperazin-1-yl)ethanol, 2-(2-(4-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)piperazin-1-yl)ethoxy)ethanol, 1-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)-3,5-dimethylpiperazine, 1-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)-2,6-dimethylpiperazine, 1-(2-(3,5-dimethylphenylthio)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3,5-dichlorophenylthio)-5-nitrophenylsulfonyl)-4-((tetrahydrofuran-2-yl)methyl)piperazine, ethyl 3-(4-(2-(3,5-dichlorophenylthio)-5-nitrophenylsulfonyl)piperazin-1-yl)propanoate, 1-(2-(3,5-dichlorophenylthio)-5-nitrophenylsulfonyl)-4-(3-methoxypropyl)piperazine, 3-(4-(2-(3,5-dichlorophenylthio)-5-nitrophenylsulfonyl)piperazin-1-yl)propanoic acid, 1-(5-nitro-2-(phenylthio)phenylsulfonyl)piperazine, 1-(2-(2,4,6-trimethylphenylthio)-5-nitrophenylsulfonyl)piperazine, 1-(5-nitro-2-(3-methylphenylthio)phenylsulfonyl)piperazine, 1-(2-(3-chlorophenylthio)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3,5-dichlorophenylthio)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3-fluorophenylthio)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3,5-bis(trifluoromethyl)phenylthio)-5-nitrophenylsulfonyl)piperazine, 1-(2-(naphthalen-2-ylthio)-5-nitrophenylsulfonyl)piperazine, N-(3,5-dimethylphenyl)-4-nitro-2-(piperazin-1-ylsulfonyl)aniline, N-(3,5-dichlorophenyl)-4-nitro-2-(piperazin-1-ylsulfonyl)aniline, 4-nitro-2-(piperazin-1-ylsulfonyl)-N-2-methylphenylaniline, 4-nitro-2-(piperazin-1-ylsulfonyl)-N-3-methylphenylaniline, 4-nitro-2-(piperazin-1-ylsulfonyl)-N-4-methylphenylaniline, N-(2-chlorophenyl)-4-nitro-2-(piperazin-1-ylsulfonyl)aniline, N-(3-chlorophenyl)-4-nitro-2-(piperazin-1-ylsulfonyl)aniline, N-(4-chlorophenyl)-4-nitro-2-(piperazin-1-ylsulfonyl)aniline, N-(2-fluorophenyl)-4-nitro-2-(piperazin-1-ylsulfonyl)aniline, N-(3-fluorophenyl)-4-nitro-2-(piperazin-1-ylsulfonyl)aniline, N-(4-fluorophenyl)-4-nitro-2-(piperazin-1-ylsulfonyl)aniline, N-(2-methoxyphenyl)-4-nitro-2-(piperazin-1-ylsulfonyl)aniline, 1-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)-4-methylpiperazine, 1-cyclohexyl-4-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)-4-phenylpiperazine, 1-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)-4-(4-methylphenyl)piperazine, 1-benzyl-4-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)piperazine, 4-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)piperazine-1-carbaldehyde, 1-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)-4-isopropylpiperazine, 1-sec-butyl-4-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)-4-(pentan-2-yl)piperazine, 1-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)-4-(pentan-3-yl)piperazine, 1-cyclopentyl-4-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)piperazine, 1-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)-4-((tetrahydrofuran-2-yl)methyl)piperazine, 1-(2-(3,5-dichlorophenoxy)-5-nitrophenylsulfonyl)-4-((tetrahydrofuran-2-yl)methyl)piperazine, 1-(2-(3,5-dimethylphenylthio)-5-nitrophenylsulfonyl)-4-((tetrahydrofuran-2-yl)methyl)piperazine, 2-(4-(2-(3,5-dichlorophenoxy)-5-nitrophenylsulfonyl)piperazin-1-yl)-N,N-diethylethanamine, 2-(4-(2-(3,5-dichlorophenoxy)-5-nitrophenylsulfonyl)piperazin-1-yl)-N,N-dimethylethanamine, 1-(2-(3,5-dichlorophenoxy)-5-nitrophenylsulfonyl)-4-( 1-methylpiperidin-4-yl)piperazine, 1-(2-(3,5-dimethylphenoxy)-5-nitrophenylsulfonyl)-4-(3,3,3-trifluoropropyl)piperazine, 1-(2-(3,5-dichlorophenoxy)-5-nitrophenylsulfonyl)-4-(3,3,3-trifluoropropyl)piperazine, 1-(2-(3,5-dichlorophenoxy)-5-nitrophenylsulfonyl)-4-(3-methoxypropyl)piperazine, ethyl 3-(4-(2-(3,5-dichlorophenoxy)-5-nitrophenylsulfonyl)piperazin-1-yl)propanoate, 1-(5-chloro-2-(3,5-dimethylphenoxy)phenylsulfonyl)piperazine, 1-(2-(3,5-dimethylphenoxy)-5-iodophenylsulfonyl)-4-ethylpiperazine, 1-(2-(3,5-dimethylphenoxy)-5-iodophenylsulfonyl)piperazine, 4-(3,5-dimethylphenoxy)-2-methyl-5-(piperazin-1-ylsulfonyl)aniline, 1-(2-(3,5-dimethylphenoxy)-5-fluorophenylsulfonyl)piperazine, 4-(3,5-dichlorophenoxy)-3-(4-(3-methoxypropyl)piperazin-1-ylsulfonyl)benzonitrile, 4-(3,5-dichlorophenylthio)-3-(piperazin-1-ylsulfonyl)benzonitrile, 4-(3,5-dichlorophenylthio)-3-(4-(3-(methylthio)propyl)piperazin-1-ylsulfonyl)benzonitrile, 3-(1,4-diazepan-1-ylsulfonyl)-4-(3,5-dichlorophenylthio)benzonitrile, 4-(3,5-dichlorophenylsulfonyl)-3-(piperazin-1-ylsulfonyl)benzonitrile, 4-(3,5-dichlorophenylamino)-3-(piperazin-1-ylsulfonyl)benzonitrile, 4-((3,5-dichlorophenyl)(methyl)amino)-3-(piperazin-1-ylsulfonyl)benzonitrile, N-(3,5-dimethylphenyl)-N-methyl-4-nitro-2-(piperazin-1-ylsulfonyl)aniline, and 1-(2-(3,5-dimethylphenoxy)-4-nitrophenylsulfonyl)piperazine.
 12. A compound of claim 11, wherein the salt is a hydrochloride, dihydrochloride, trihydrochloride, or a mono-, di- or tri-trifluoroacetate.
 13. A compound of claim 12, wherein the salt is a hydrochloride.
 14. A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable carriers or excipients.
 15. The pharmaceutical composition of claim 14, wherein the compound, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof is in unit dosage form.
 16. A method of treating a CCR3 related disease or disorder comprising administering a compound of claim 1, wherein the disease or disorder is selected from the group consisting of arthritis, asthma, allergic rhinitis, atopic dermatitis, athero sclerosis, Grave's disease, HIV infection, lung granuloma, and Alzheimer's disease.
 17. A compound, its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof, wherein the compound is selected from the group consisting of: 1-(2-(3,5-dimethylphenoxy)-5-(piperazin-1-ylsulfonyl)phenylsulfonyl)piperazine, 1-(2-(3,5-dimethylphenoxy)-5-(methylsulfonyl)phenylsulfonyl)piperazine, 1-(2-(3,5-dimethylphenoxy)phenylsulfonyl)piperazine, (4(3,5-dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)phenyl)(piperazin-1-yl)methanone, 1-(2-(3,5-dimethylphenoxy)-5-(trifluoromethyl)phenylsulfonyl)piperazine, 1-(2-(3,5-dichlorophenoxy)-4-methyl-5-nitrophenylsulfonyl)piperazine, 1-(2-(3,5-dimethylphenoxy)-4-(trifluoromethyl)phenylsulfonyl)piperazine, 1-(2-(3,5-dimethylphenoxy)-4-methoxy-5-nitrophenylsulfonyl)piperazine, 1-(2-(3,5-dimethylphenoxy)-4-methoxyphenylsulfonyl)piperazine hydrochloride, 1-(2-(3,5-dimethylphenoxy)-4-methoxy-5-nitrophenylsulfonyl)piperazine, 1-(2-(3,5-dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)aniline, 1-(5-chloro-2-(3,5-dimethylphenoxy)-4-methylphenylsulfonyl)piperazine, 4-(3,5-dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)phenol, 1-(2-(3,5-dimethylphenoxy)-5-(methoxyphenylsulfonyl)piperazine, 1-(2-(3,5-dimethylphenoxy)-5-(fluorophenylsulfonyl)piperazine, N-(4-(3,5-dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)phenyl)acetamide, N-(4-(3,5-dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)phenyl)pivalamide, N-(4-(3,5-dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)phenyl)3-methylbutanamide, N-(4-(3,5-dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)phenyl)benzamide, N-(4-(3,5-dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)phenyl)-4-methylbenzamide, N-(4-(3,5-dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)phenyl)a-1-naphthamide, N-(4-(3,5-dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)phenyl)-3-phenylpropanamide, N-(4-(3,5-dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)phenyl)thiophene-2-carboxamide, 1-(5-bromo-2-(3,5-dimethylphenoxy)phenylsulfonyl)piperazine, 4-(3,5-dichlorophenoxy)-N,N-dimethyl-3-(piperazin-1-ylsulfonyl)benzamide, 4-(3,5-dimethylphenoxy)-N,N-dimethyl-3-(piperazin-1-ylsulfonyl)benzamide, 5-(3,5-dimethylphenoxy)-6-(piperazin-1-ylsulfonyl)-1H-indole, 2-chloro-4-(3,5-dimethylphenoxy)-5-(piperazin-1-ylsulfonyl)benzonitrile, 2-chloro-4-(3,5-dichlorophenoxy)-5-(piperazin-1-ylsulfonyl)benzonitrile, 4-(3,5-dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)benzoic acid, 3-(4-(tert-butoxycarbonyl)piperazin-1-ylsulfonyl)-4-(3,5-dichlorophenoxy)benzoic acid, 4-(3,5-dichlorophenoxy)-3-(piperazin-1-ylsulfonyl)benzoic acid, 4-(3,5-dichlorophenoxy)-3-(piperazin-1-ylsulfonyl)benzamide, methyl 4-(3,5-dimethylphenoxy)-3-(piperazine-1-ylsulfonyl)benzoate, 2-chloro-4-(3,5-dimethylphenoxy)-5-(piperazin-1-ylsulfonyl)benzamide, 4-(3,5-dichlorophenoxy)-3-fluoro-5-(piperazin-1-ylsulfonyl)benzamide, 4-(3,5-dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)methanol, N-(2-cyanoethyl)-4-(3,5-dimethylphenoxy)3-(piperazin-1-ylsulfonyl)benzamide, N-(3-amino-3-oxopropyl)-4-(3,5-dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)benzamide, 3-(5-3,5-dimethylphenoxy)-3-(piperazin-1-ylsulfonyl)phenyl)-1H-tetrazol-1-yl)propanenitrile, 1-(2-(3,5-dimethylphenoxy)-5-(1H-tetrazol-5-yl)phenylsulfonyl)piperazine, and 1-(4-bromo-2-(3,5-dimethylphenoxy)phenylsulfonyl)piperazine.
 18. A pharmaceutical composition comprising a compound of claim 17 and one or more pharmaceutically acceptable carriers or excipients.
 19. A method of treating a CCR3 related disease or disorder comprising administering a compound of claim 17, wherein the disease or disorder is selected from the group consisting of arthritis, asthma, allergic rhinitis, atopic dermatitis, athero sclerosis, Grave's disease, HIV infection, lung granuloma, and Alzheimer's disease. 